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REVIEWS
María González-Rodríguez a,b,1,
Clara Ruiz-Fernández a,c,1, Alfonso Cordero-Barreal a,d,
Djedjiga Ait Eldjoudi a, Jesus Pino a,e,2,⇑,
Yousof Farrag a,2,⇑, Oreste Gualillo a,2,⇑
a
SERGAS (Servizo Galego de Saude) and NEIRID Lab (Neuroendocrine Interactions in
Rheumatology and Inflammatory Diseases), Research Laboratory 9,
IDIS (Instituto de Investigación Sanitaria de Santiago), Santiago University Clinical Hospital,
Santiago de Compostela, Spain
b
International PhD School of the University of Santiago de Compostela (EDIUS),
Doctoral Programme in Drug Research and Development, Santiago de Compostela, Spain
c
International PhD School of the University of Santiago de Compostela (EDIUS),
Doctoral Programme in Medicine Clinical Research, Santiago de
Compostela, Spain
d
International PhD School of the University of Santiago de Compostela (EDIUS),
Doctoral Programme in Molecular Medicine, Santiago de Compostela, Spain
e
Departamento de Cirurgía y Especialidades Médico-Cirúrgicas àrea de
Traumatología e Ortopedia, Universidade de Santiago de Compostela, Santiago
de Compostela, Spain
Abbreviations: ADAMTS, A disintegrin and metalloproteinase with thrombospondin motifs; AF,
Annulus fibrosus; AMPK, AMP-activated protein kinase; AS, Ankylosing Spondylitis; APJ, Angiotensin
domain type 1 receptor-associated proteins.; BMC, Body Mineral Content; BMD, Bone mineral density;
BMMs, Bone marrow-derived monocytes; BM-MSCs, Bone marrow-mesenchimal stem cells; CAMKII,
CaM kinase II; COX-2, Cyclooxygenase-2; CRP, C-reactive protein; DAS28, 28-joint count Disease
Activity Score; eNAMPT, Extracellular nicotinamide phosphoribosyltransferase; ERK, Extracellular-signalregulated kinase; ESR, Erythrocyte sedimentation rate; ICAM-1, Intercellular Adhesion Molecule 1; ICTP,
Carboxyl-terminal telopeptide of type I collagen; IFN-c, Interferon gamma; IPFP, Infrapatellar fat pad;
IGF-1, Insulin-like growth factor; IKKab, Inhibitor of nuclear factor kappa-B kinase subunit alpha beta; IL,
Interleukin; iNAMPT, Intracellular nicotinamide phosphoribosyltransferase; IVDD, Intervertebral disc
degeneration; JNK, cJun N-terminal kinases; LCN-2, Lipocalin-2; LKB1, Liver kinase B1; MCP-1,
Monocyte chemoattractant protein 1; MetS, Metabolic syndrome; MMP, Matrix Metallopeptidase;
mPGES-1, Microsomal prostaglandin E synthase-1; MSC, Messenchimal stem cells; NAMPT, Pre-B cell
colony-enhancing factor of nicotinamide phosphoribosyltransferase; NF-jB, Nuclear factor- jB; NO,
Nitric oxide; OA, Osteoarthritis; P1NP, Procollagen 1 amino-terminal propeptide; p38-MAPK, p38
mitogen-activated protein kinases; PBMCs, peripheral blood mononuclear cells; PGE2, Prostaglandin E2;
PI3K, phosphoinositide 3-kinase; PKB, Protein kinase B; PPAR, peroxisome proliferator-activated
receptor; RA, Rheumatoid arthritis; RANKL, Receptor Activator for Nuclear Factor-jB Ligand; RASFs, RA
synovial fibroblasts; ROS, Reactive oxygen species; SLE, Systemic lupus erythematosus; STAT, Signal
transducer and activator of transcription; TGF-b, Transforming growth factor beta; TIMP-2, Tissue
inhibitor of metalloproteinase 2; TLR4, Toll-like receptor 4-dependent; TNF-a, Tumor necrosis factor a;
VCAM-1, Vascular cell adhesion molecule 1; WAT, White adipose tissue.
KEYNOTE
Adipokines as targets in musculoskeletal
immune and inflammatory diseases
Dr. Oreste Gualillo graduated in
pharmaceutical chemistry and technology from the School of Pharmacy, University ‘Federico II’, Naples,
Italy. He was awarded a PhD in
pharmacology in 1996. He received
postdoctoral training in molecular
endocrinology at the Necker School
of Medicine, INSERM U344, in Paris.
From 1998 to 2000, he was a Marie
Curie
TMR30
post-doctoral
researcher at the Department of
Medicine, Molecular Endocrinology Division of the University of
Santiago de Compostela. In 2001, he set up his own research
group at the Santiago University Clinical Hospital, Division of
Rheumatology. He is currently a staff researcher in SERGAS in the
Spanish National Health System, at Area Sanitaria de Santiago de
Compostela e Barbanza, Santiago University Clinical Hospital,
heading the Neuroendocrine Interactions in Rheumatology and
Inflammatory Diseases (NEIRID) group of IDIS (Instituto de Investigación Sanitaria de Santiago de Compostela). He works on the
regulation and signal transduction of adipokines in inflammatory,
rheumatic, and musculoskeletal diseases.
Dr. Yousof Farrag graduated in
pharmaceutical sciences from the
University of Alexandria, Egypt. He
was awarded a PhD in applied physics in 2018 from the University of
Coruña, Spain. He received postdoctoral training in the Institute of
Polymer Physics of the Spanish
National Research Council (CSIC). He
is
currently
a
postdoctoral
researcher of the Sara Borrell program of the Spanish National Institute of Health (Instituto Nacional de Salud Carlos III) leading a
project on the role of specific biomaterials and hydrogels for drug
delivery and regenerative medicine, with a particular emphasis to
cartilage applications. He is also a staff researcher in the NEIRID
group, IDIS.
⇑ Corresponding authors.Pino, J. (jesus.pino@usc.es), Farrag, Y. (yousof.farrag.zakaria@sergas.es), Gualillo, O. (oreste.gualillo@sergas.es).
1
2
These authors contributed equally to this work.
These authors contributed equally to this paper and share senior co-authorship.
1359-6446/Ó 2022 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.drudis.2022.103352
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Adipokines are the principal mediators in adipose signaling.
Nevertheless, besides their role in energy storage, these
molecules can be produced by other cells, such as immune
cells or chondrocytes. Given their pleiotropic effects, research
over the past few years has also focused on musculoskeletal
diseases, showing that these adipokines might have relevant
roles in worsening the disease or improving the treatment
response. In this review, we summarize recent advances in our
understanding of adipokines and their role in the most
prevalent musculoskeletal immune and inflammatory
disorders.
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Dr. Jesus Pino graduated in medicine in 1979 and obtained a specialty degree in orthopedic surgery
in 1986. He was awarded a PhD in
medicine in 2008 studying physical
and biological properties of new
biomaterials in orthopedic surgery.
He is currently surgeon at the
orthopedic surgery division of the
Santiago University Clinical Hospital.
He is also a professor of orthopedic
surgery at the University of Santiago, Faculty of Medicine. He is also a staff researcher in the NEIRID
group, IDIS.
Keywords: Adipokines; Inflammation; Arthritis; Musculoskeletal diseases; Metabolic Syndrome
Introduction
Adipose tissue is no longer considered just an energy reservoir: it
also has a relevant role as a complex multifunctional endocrine
organ releasing bioactive polypeptides called adipokines. Over
the past few decades, adipokines were shown to have a role in
inflammation, immunity, blood pressure, and lipidic and energetic metabolism. They are released principally by white adipose
tissue (WAT), mainly via adipocytes, although also by preadipocytes, adipose tissue-infiltrated immune cells, and other cell
types within adipose tissue. In addition, they can also be synthesized in other tissues, such as bone, cartilage, and immune cells.1
Over the past few decades, the relevance of adipokines in
inflammatory mechanisms, and metabolic, cardiovascular, and
musculoskeletal diseases (MSDs) has been assessed. Many
adipokines, such as leptin, resistin, or adiponectin, are related
not only to metabolic diseases because of their role regulating
energetic homeostasis, but also to inflammatory diseases because
they might also have pro- or anti-inflammatory effects.
Musculoskeletal and immune-inflammatory diseases, such as
osteoarthritis (OA), rheumatoid arthritis (RA), intervertebral disc
degeneration, and osteoporosis, have an increasing impact in
developed countries because of lifestyle factors, obesity incidence, and increased life expectancy. Over 344 million cases of
OA and 14 million cases of RA were reported in 2019 worldwide.2
These chronic diseases are also associated with significant economic burdens. Most of these diseases cannot be cured; instead,
current therapies only treat symptoms and entail complex surgical interventions that are associated with slow recuperation and
time-consuming rehabilitation.
These immune-inflammatory disorders have been described
to be associated with high levels of certain adipokines in synovial
fluid and blood. Recent research correlates adiponectin with
bone destruction and RA risk, reports increased leptin and resistin levels in patients with OA, and reveals a role for chemerin
in osteoporosis promoting osteogenic differentiation and bone
formation. In this review, we summarize recent discoveries
related to the impact of adipokines in MSDs, focusing on the
principal adipokines, such as leptin, adiponectin, visfatin, resistin, or lipocalin 2 (LCN2), and new adipokines discovered more
recently.
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Adipokines
Leptin
Leptin is a 16-kDa nonglycosylated hormone encoded by the
obese (ob) gene and synthesized mainly by WAT. Levels of circulating leptin are dependent on the WAT mass in addition to the
nutritional status. Glucocorticoids, insulin, sex steroids, cytokines and toxins are reported to be involved in the regulation of
leptin expression.3–6 Leptin receptors (Ob-R) are a class I cytokine
receptor family encoded by the diabetes (db) gene. At least six
Ob-R isoforms have been identified: four short isoforms (ObRa, Ob-Rc, Ob-Rd, and Ob-Rf), a soluble isoform (Ob-Re), and a
long isoform (Ob-Rb), which has a full intracellular domain that
affects signal transduction via the canonical Janus kinase (JAK)
and signal transducer and activator of transcription (STAT) signaling pathways. They share the same extracellular binding
domains but have different cytoplasmic domain lengths. In addition, leptin receptors act via extracellular signal-regulated kinases
(ERKs) 1/2, c-Jun N-terminal kinases (JNKs), p38 mitogenactivated protein kinase (MAPK), phosphoinositide 3-kinase
(PI3K)/Akt pathways, protein kinase C (PKC), and Src homology
region 2-containing protein tyrosine phosphatase 2 (SHP2)/growth factor receptor-bound protein 2 (GRB2). Leptin receptors
are expressed throughout the innate and adaptive immune system cells, blood vessels, and cardiomyocytes.7
Previous studies showed elevated leptin levels in the serum
and synovial fluid of patients with RA compared with healthy
controls.8 Another study reported a significant correlation
between serum leptin and reduced joint damage, RA duration,
and the levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), 28-joint count Disease Activity Score (DAS28),
tumor necrosis factor a (TNFa), and interleukin 6 (IL6).9 Nevertheless, no significant differences in plasma and synovial fluid
leptin levels were found between patients with RA and healthy
individuals; neither were correlations to disease duration, disease
activity, CRP, ESR, radiographic factor, erosive or non-erosive
RA.10 Leptin was reported to promote RA fibroblast-like synoviocyte (FLS) migration and angiogenesis via increasing the production of reactive oxygen species (ROS). Antagonists of IL6, IL1,
and TNF reduced the leptin-induced ROS production and FLS
migration.11 RA has been associated with regulatory CD4+Foxp3+
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T cells (Treg) defects. Leptin receptors are expressed on the surface of Treg cells. Leptin monoclonal antibodies neutralize leptin
and cause reversion of the hyper-responsiveness to anti-CD3 and
anti-CD28 stimulation and the promotion of Treg expansion.
This proliferation can be reversed using recombinant leptin.
These results suggest that leptin acts as a negative signal for the
expansion of Foxp3+CD25+CD4+ and might be a potential therapeutic approach for autoimmune diseases.12
Several studies showed a correlation between leptin levels in
serum or synovial fluid and OA. Leptin levels in patients with
knee OA were higher than in controls, with even higher expression in female than in male patients.13 Another study also
reported a correlation between leptin levels and WOMAC-pain
score and the radiographic stage of knee OA, enhancing OA progression.14 The leptin receptor Ob-Rb is highly expressed in OA
cartilage.15 Moreover, leptin was reported to activate the mTOR
pathway in chondrocytes, leading to the inhibition of autophagy, which, in turn, was reversed by the blockade of mTOR.16
Higher amounts of leptin secretions in synovium and infrapatellar fat pad (IPFP) were reported in patients with OA with metabolic syndrome (MetS).17 Leptin mediates the association of OA
with obesity, a potent risk factor for OA incidence and progression.18 Accordingly, significantly higher leptin levels were
reported only in patients with knee OA with body mass index
(BMI) > 30.14
In a rat model of osteoporosis, Zheng et al. showed that leptin
overexpression in bone marrow stromal cells enhanced periodontal regeneration.19 Another study showed that miR29
decreased leptin expression in adipocyte development and
reduced high fat diet-induced leptin expression in bone, controlling leptin signaling to maintain bone anabolism.20
Segar et al. showed that leptin can interfere with intervertebral
disc cell metabolism, increasing protease and nitric oxide (NO)
production. It also synergized with pro/inflammatory mediators
enhancing metalloproteinase, NO, and cytokine production21
Another study showed that in mice with type 2 diabetes mellitus
induced by leptin receptor knockout, intervertebral disc degeneration (IVDD) was triggered by higher levels of matrix metallopeptidase (MMP)-3 and cell apoptosis promotion.22 Regarding leptin
signaling in IVDD, a study showed that, in leptin receptorknockout mice, only female animals presented altered disc morphology, indicating delayed disc cell proliferation and differentiation, instead of degeneration.23
Recent studies reported serum leptin levels to be higher in
patients with systemic lupus erythematosus (SLE), although
there was no observed correlation with disease activity.24–25 As
in RA, leptin systemic levels were associated with a deficiency
of Treg cells.26 B cells stimulated with either leptin or serum of
patients with SLE produced increased levels of IL6, IL10, and
TNFa.27 Anti-leptin antibodies were able to reverse the Treg deficiency and cytokine overproduction. A recent study in mice indicated that leptin deficiency can protect against SLE, although, in
a spontaneous SLE mouse model, leptin can accelerate the
pathology.28
Several studies did not find a correlation between serum leptin
levels and ankylosing spondylitis (AS) development.29–30 Instead,
leptin was associated with bone protection and new bone formation in AS.31 This might explain why women, who normally
have higher systemic leptin levels compared with men, have less
spinal structural damage than men in AS.32
Adiponectin
Adiponectin is the most abundant adipokine in human blood.33
It is synthesized mainly by WAT and can be found in circulation
in different isoforms, being the high-molecular-weight isoform
the most important for glucose homeostasis.34 It has a positive
role in metabolism, where its levels are negatively correlated with
obesity, weight, and diabetes.35 Adiponectin also increases insulin sensibility in liver and muscle.36 In muscle cells, adiponectin
triggers the oxidation of fatty acids through peroxisome
proliferator-activated receptor a (PPARa) and AMP-activated protein kinase (AMPK).37–38 These circulation levels of adiponectin
are lower in obese patients and can be regulated with drugs such
as thiazolidinediones.36
Adiponectin has two main classical receptor subtypes, AdipoR1 and AdipoR2, on chromosomes 1, locus 1p36.13-q41,
and 12, locus 12p13.31, respectively.39 As targets of the globular
and full-length adiponectin, both receptors are associated with
the activation of PPARa, PPARc, AMPK, glucose uptake, and fatty
acid oxidation.36,40 AdipoR1 is related to the stimulation of
AMPK, p38-MAPK, JNK, PPARa, and nuclear factor-kB (NF-jB)
pathways, which inhibit gluconeogenesis and stimulate fatty
acids oxidation. AdipoR2 is related to the action of PPAR pathways dissipating energy, stimulating fatty acids oxidation, and
decreasing inflammation and oxidative stress.41 Adiponectin
was also described to inhibit the inflammatory response, suppressing Toll-like receptor (TLR)-4-mediated NF-jB activation,
polarizing M1 macrophages to M2, and T helper (Th)-1/Th17
to Th2/Treg.42
Multiple researchers have demonstrated the importance of
adiponectin in the pathogenesis of synovitis in patients with
RA. For instance, the group of Kusunoki found that adiponectin
induces cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) expression, with increases in PGE2
production by RA synovial fibroblasts (RASFs).43 Adiponectin
also enhances the production of IL6 and MMP1 through AMPK,
p38, IKKab, and NF-jB in human synovial fibroblasts.44–45 Qian
et al. suggested that adiponectin levels from synovial tissue in
patients with RA can induce the production of osteopontin,
which causes bone erosion.46 Some researchers also hypothesized that adiponectin could be useful as clinical biomarker in
osteoporosis because of its role in bone metabolism.47–48
Compared with healthy controls, adiponectin showed higher
levels in plasma and synovial fluid in patients with RA,46,49
whereas other studies showed no correlation with the clinical
outcome of the disease.50–51 In addition, adiponectin levels were
not even correlated to DAS28 or CRP levels.52
Most of the studies in cohorts of patients with OA showed
that adiponectin levels are higher in these patients compared
with controls; for instance, Wu et al. showed that adiponectin
inhibits bone marrow-derived monocyte (BMM) growth and proliferation in a dose-dependent manner.53 Recently, the group of
Orellana showed that the level of adiponectin in synovium was
positively correlated with clinical severity in women with knee
OA, and also with the production of IL6.54
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The levels of adiponectin in IPFP were reported to be higher
compared with subcutaneous adipose tissue in patients with
OA.55 The particular profile of cytokines from adjacent cartilage
in these patients could contribute to paracrine inflammation
through the secretion of IL6/sIL6R.55
Adiponectin receptors are present in human chondrocytes,56
being reported to improve chondrogenesis and to be downregulated in patients with OA.57–58 In models of in vitro chondrogenesis (e.g., ATDC5 cells, derived from mouse terato-carcinoma),59
this adipokine increased type II collagen, Runx2, proliferation,
synthesis of proteoglycans, and matrix mineralization.60
Plasma adiponectin levels were also reported to be higher in
patients with OA than in healthy controls.61 These higher levels
are correlated with the upregulation of MMP13 and PGE2 expression, because adiponectin increases the activity and production
of PGE2,62 as well as proinflammatory mediators, such as NO,
IL6, and other metalloproteinases,44,63 which indicates that this
adipokine contributes to the pathology of OA. By contrast, adiponectin is being studied as an anti-inflammatory adipokine
with anabolic functions increasing TIMP2 and decreasing
MMP13 via IL1b.64
Adiponectin is able to increase adhesion molecules [e.g., intracellular adhesion molecule-1 (ICAM-1)] in human OA synovial
fibroblasts.65 These adhesion molecules are important for the
progression of OA because they mediate fibroblast adhesion
and infiltration during OA pathogenesis. These molecules are
activated via liver kinase B1 (LKB1)/CaM kinase II (CAMKII),
AMPK, and the AP1 pathway, resulting in monocyte adhesion
to human OA synovial fibroblasts.65
Bone-forming cells were reported to express adiponectin and
its receptors,66 indicating the link between this adipokine and
bone metabolism. Adiponectin levels were negatively correlated
with bone mineral density (BMD) and body mineral content
(BMC) levels.67 In addition, patients with MetS showed lower
adiponectin levels compared with controls, which supports the
negative correlation of adiponectin with BMD.68
Adiponectin is described to have opposite effects in bone: on
the one hand, it stimulates the proliferation and mineralization
of human osteoblasts via the p38 MAPK signaling pathway. On
the other hand, it activates osteoclasts through RANKL and inhibits osteoprotegerin.69 In agreement with this, in the RAW 264.7
murine macrophage cell line, adiponectin was described to inhibit osteoclastogenesis and bone resorption, inhibiting the NF-jB
and p38 signaling pathways, which are vital for osteoclast production.70 The group of Wang showed that adiponectin
enhances osteogenesis via the Wnt/b-catenin pathway in bone
marrow mesenchymal stem cells (BMSCs).71 New studies suggest
that the role of adiponectin in bone metabolism depends on sex
hormone levels because adiponectin levels are negative correlated with BMD in women, with no correlation in men.72
In human osteoblastic cells, adiponectin resulted in the
upregulation of oncostatin M expression via the PI3K, Akt, and
NF-jB pathways,73 which suggests it as a target for RA treatment.
Krumblholz and colleagues examined adiponectin effects in
bone, indicating that adiponectin upregulates the expression of
IL8 and MMP9 in osteoclasts, and inhibits osteoprotegerin
mRNA in osteoblasts, showing that adiponectin reduces mineralization and increases resorption in bone.74
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In AS, adiponectin levels are not correlated with the disease,
although these levels are sex dependent and might be affected
by androgens.75 Adiponectin levels were also not correlated with
acute-phase reactant levels (e.g., CRP or ESR). Many studies
reported that serum levels of adiponectin in patients with AS
are not significantly different.30,32 Nevertheless, one study
showed that adiponectin levels might be related to radiographic
spinal cord evolution in patients with AS.32 Further studies are
needed to clarify these relationships.
Adiponectin levels in patients with SLE show no increase
compared with healthy controls, which indicates no correlation
with the disease.76–79
Visfatin
Visfatin is a cytokine that was first isolated and characterized
from a human peripheral blood lymphocyte cDNA library.80 It
is also known as pre-B cell colony-enhancing factor of nicotinamide phosphoribosyltransferase (NAMPT), and is produced
mainly by visceral adipose tissue, although its expression was
also reported in adipose tissues, liver, muscle, and immune
cells.81 Visfatin is correlated with obesity, with higher levels in
obese subjects.82 It was also reported to be a useful protein for
diagnostics, prognostics, and therapeutics in cardiovascular
diseases.83
Visfatin inhibits insulin signaling, and the STAT3 and NF-jB
pathways in the human liver cancer cell line HepG2;84 however,
in osteoblasts, visfatin realized its insulin-like function via phosphorylation of the insulin receptor.85 Although there is no visfatin receptor described thus far, it was reported to bind to, and
activate, the insulin receptor, mimicking the effect of insulin.81
Visfatin is involved in various signaling pathways and can be
found in both intracellular (iNAMPT) or extracellular forms
(eNAMPT). The extracellular form has a role in signaling pathways and is involved in some intracellular signaling cascades.83
The proinflammatory effects of visfatin in chondrocytes can
be explained by activation of the insulin receptor signaling pathways.86 eNAMPT activates the ERK/MAPK pathway in chondrocytes, inhibiting insulin-like growth factor (IGF1) independent
of the IGF1 receptor.87
The role of visfatin in bone metabolism has been studied in
different populations, but remains controversial.88–89 For example, there was no significant correlation between visfatin and
BMD in women with postmenopausal osteoporosis.90
Patients with MetS have higher levels of visfatin compared
with controls, being positively associated with BMD, but only in
men.68 Recent studies showed that visfatin does not affect BMD
in women with primary osteoporosis.90 Terzoudis et al. described
for the first time that visfatin levels and the presence of osteoporosis are positively associated in inflammatory bowel disease.91
Moreover, visfatin has been identified as a positive predictor of
BMD in young survivors of acute lymphocytic leukemia.89 The
suppression of visfatin was recently discovered to be accompanied
by the suppression of osteoblast differentiation of bone marrow
mesenchymal stem cells (BM-MSCs), indicating visfatin as a possible marker of osteoblast differentiation.92 At present, visfatin
involvement in bone metabolism is not clear because of discrepancies between studies.
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Tsiklauri et al. found that visfatin is involved in matrix production in MSC differentiation and reduction of collagen type I
expression, and can be an important player in the pathophysiology and development of osteoporosis, producing bone fragility.93
In addition, this research suggests that bone remodeling can be
affected by visfatin producing proinflammatory factors, resulting
in an MMP/TIMP imbalance.93 Visfatin has been reported to promote osteogenesis through the upregulating of Runx2 transcription.94 By contrast, visfatin also can increase its expression
during inflammation.95 The suppression of visfatin in mouse
BM-MSCs downregulates osteoblastogenesis, inhibits some osteoblast differentiation markers, alkaline phosphatase activity, and
matrix mineralization of these cells.92 Recent studies of the mechanism of this adipokine demonstrated that visfatin suppresses
RANKL-induced osteoclast differentiation by interfering with signaling pathways related to survival, such as JNK or Akt.96
Patients with RA or OA show an increase in the levels of visfatin expression in the synovium, being higher in RA.97 Visfatin
was also demonstrated to increase the expression of several
proinflammatory cytokines, such as IL1b, IL6, IL17A,TNFa,
MMP1, MMP13, and antioxidant enzymes (SOD2, CAT, and
NRF2).98–99 In particular, visfatin was reported to upregulate
IL6 and TNFa expression, suppressing the expression of miR199a-5p via the ERK, p38, and JNK pathways in human synovial
fibroblasts.100 Recently, visfatin was found to upregulate ICAM1
and stimulate monocyte adhesion to OA synovial fibroblasts by
inhibiting the synthesis of miR320a via the AMPK and p38 pathways.101 These findings indicate a potential proinflammatory
role of visfatin in synovium.
The presence of visfatin and its relation with cartilage catabolism and inflammation were reported in patients with OA.102–103
Recent studies have discovered that visfatin is principally located
in OA synovium in the human OA joint in its enzymatically
active conformation.103 In chondrocytes, visfatin was shown to
stimulate the secretion of IL6, Kc, and monocyte chemoattractant protein 1 (MCP1),103 which are important factors for the
progression of OA.
Results from meta-analysis studies showed higher visfatin
levels in patients with RA than healthy controls, and even higher
levels in patients with joint erosion.52,104–106 Visfatin, DAS28,
and CRP levels were found to be positively correlated.52 It appears
that overexpression of this adipokine inhibits osteoclast formation via Nfatc1.107–108 For instance, in a collagen-induced arthritis
murine model, visfatin-deficient mice showed less bone destruction, inflammation, and RA progression.107 In conclusion, visfatin could be used as an inflammatory biomarker for RA,
although other cytokines, such as chemerin, are more specific.109
Injecting visfatin to rat models aggravated the status of IVDD,
as reported by the group of Cui.110 The same group showed that
human nucleus pulposus cells treated with visfatin decreased collagen II and aggrecan levels, whereas MMP13 and IL6
increased.110 More studies are needed to confirm these findings.
The levels of visfatin in patients with AS were higher than in
healthy controls. This adipokine, as seen with adiponectin, is not
correlated with acute-phase reactant levels (e.g., CRP or ESR).75 A
clinical study in patients with AS without diabetes under TNFa
antagonist therapy (infliximab) did not show any relation
between visfatin and AS activity and systemic inflammation.111
Levels of visfatin and the progression of SLE do not appear to
be correlated.78 By contrast, previous studies found that the
levels of visfatin in patients with SLE are higher than in controls
but not related to inflammation.112
Resistin
Human resistin is a 12.5-kDa cysteine-rich adipokine that
belongs to the family of ‘resistin-like molecules’ and is encoded
by RETN. Two quaternary forms of resistin are present in
humans: an abundant high-molecular-weight hexamer and a
more bioactive trimer that induces hepatic insulin resistance as
well as inflammation. Resistin is mainly expressed by monocytes
and macrophages activated with lipopolysaccharide (LPS), IL1b,
IL6, TNFa, and resistin itself. It is also expressed to a lesser extent
by pancreatic b cell, lung cells, and placental tissue. Resistin
enhances the expression of vascular cell adhesion molecule 1
(VCAM1), ICAM1, pentraxin 3, MCP1, TNFa, IL6, and IL12
through a NF-jB-dependent pathway in vascular endothelial
cells, promoting leukocyte adhesion and the inflammatory
response. Resistin competes with LPS for binding to TLR4 and
adenylyl cyclase-associated protein 1 (CAP1). Resistin can signal
through different receptors depending on the tissue and cell type
[an isoform of decorin involved in WAT expansion, tyrosine
kinase-like orphan receptor 1 (ROR1) in 3 T3-L1 cells, or IGF1
receptor (IGF1R) in fibroblasts]. Resistin activates G-proteindependent signaling, PI3K/Akt pathway, adenylate cyclase/
cAMP/PKA pathway, PKC, and extracellular Ca21 signaling
through L-type voltage-sensitive Ca2+.41
Resistin can increase chemokine production by fibroblast-like
synoviocytes in synovial tissue through the CAP1receptor.113 Li
et al. reported that, in a Chinese population, resistin gene polymorphisms could determine genetic predisposition to RA.114
Another study provided further insights showing that high serum
resistin levels were correlated with active inflammatory disease
and faster radiological progression. They showed that TNFa production was increased by resistin in macrophages.115 A recent
study did not find any association of resistin plasma levels with
plasma chemokines, markers of inflammation, or disease activity
in patients with newly diagnosed but untreated RA.116
Alissa et al. demonstrated that serum resistin levels were
higher in patients with primary knee OA than in healthy controls. Resistin levels were also correlated with inflammatory
markers and adiposity.117 A recent study showed that, in OA synovial fibroblasts, resistin upregulates VCAM-1 and enhances
monocyte adhesion. Its signaling occurs via the p38, PKCa, and
JNK pathways.118 Chen et al. described how resistin expression
is higher in OA knee synovial tissue than in controls. This adipokine also triggers IL1b and TNFa expression in OA synovial
fibroblasts through the ERK and MEK signaling pathways.119 In
patients with OA, resistin was significatively increased only in
those with high BMI.14 A recent study on patients with knee
OA associated resistin-related metabolic inflammation with some
knee structural changes, and confirmed the lack of evidence linking it with OA symptoms.120 A recent study also found that
serum resistin levels are higher in postmenopausal women with
low BMD and with osteopenia.121
Resistin was proved to increase ADAMTS5 expression in rat
nucleus pulposus (NP) cells in a dose and time-dependent way,
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and that the p38 MAPK pathway is involved in the signaling.122
Another study confirmed these results in human NP cells, showing that, by triggering the p38 MAPK and NF-jB pathways, resistin, which binds TLR4, can upregulate CCL4 expression,
triggering macrophage infiltration.123
A study assessing this issue did not show a significant association between resistin serum levels and SLE disease activity.124
Nevertheless, there are some studies that present contradictory
data. Chougule et al. found that serum resistin levels were higher
in patients with SLE than in healthy controls and that, in the SLE
group, increased resistin levels correlated with patients presenting renal involvement.78 Supporting this study, a meta-analysis
review stated that serum levels of resistin positively correlated
with SLE disease activity.125 Besides confirming the correlation
between patients with renal SLE involvement and higher resistin
levels, resistin increment was also related to proteinuria and high
creatinine levels.126 Finally, elevated serum resistin levels have
been associated with MetS in patients with SLE.127–128
Resistin levels were also found higher in serum from patients
with AS than in healthy controls. These high levels were correlated with radiographic progression and AS development, suggesting that it has a role in the pathogenesis of new bone
formation instead of inflammation.30–31
Lipocalin-2
LCN2 is a glycoprotein produced mainly by WAT, although it is
also expressed in spleen, liver, chondrocytes, and immune cells.
It was first identified in human neutrophils granules and mouse
kidney cells and is encoded by a gene located at the chromosome
locus 9q34.11. It circulates as a 25-kDa monomer, 46-kDa
homodimer, or as a covalent complex with MMP9, blocking
MMP9 autodegradation. There are two proposed receptors to
LCN2: the megalin/glycoprotein GP330, an LDL receptor that
also binds to the human LCN2, and the transporter protein
SLC22A17 (24p3R), which binds to mouse LCN2.7
Recently, LCN2 levels in serum were reported to be significantly higher in patients with RA than in healthy individuals.
Within the group of patients with RA, higher LCN2 levels were
positively correlated with high modified Larsen score (a scoring
system based on structural damage observed on radiography),
which can indicate an association with joint damage. However,
no significant differences were observed between LCN2 serum
levels and disease activity. Serum LCN2 levels in patients with
RA were not directly correlated with inflammatory activation.129
LCN2 has been also suggested to be involved in the antiinflammatory regulation of M1/M2 polarization and in the
increases in Treg cell proliferation. Another factor contributing
to RA pathophysiology is the increase in LCN2 expression in
neutrophils, caused by granulocyte–macrophage colonystimulating factor.7 LCN2 levels in synovial fluid were higher
in patients with RA than with OA. Despite these recent findings,
the role of LCN2 in the development of the disease continues to
be largely unknown.
LCN2 can contribute to the degradation of the cartilage
matrix in OA via maintaining MMP9 activity.130 There is also evidence that LCN2 expression is inhibited throughout osteoblast
differentiation and induced in osteoblasts and chondrocytes
exposed to an OA-related inflammatory environment.131 The
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transcription factor E74-like factor 3 and NF-jB modulate the
expression of LCN2 in chondrocytes. Of note, glucocorticoids
used in OA and RA treatment were reported to increase LCN2
expression via corticoid receptor and PI3K, ERK1/2 and JAK2
pathways in immortalized mouse chondrocytes.7 Despite the
increase in LCN2 levels in synovial fluid of OA knees, Maurizi
et al. did not observe differences in LCN2 serum levels between
patients with OA and normal BMD and healthy subjects.132
Although LCN2 has been associated with OA pathogenesis, no
study has addressed its effects on catabolic or anabolic genes during OA pathogenesis. An in vivo study concluded that, in OA cartilage, Lcn2 upregulation was not sufficient or necessary for
cartilage destruction in mice.133 However, a recent study found
a significant upregulation of LCN2 in menisci during OA, suggesting that early-stage OA is affected by LCN2 activation in
the menisci but not in chondrocytes.134
Evidence showed neither a correlation between LCN2 serum
levels and BMD in patients with OA nor changes in LCN2 serum
levels between patients with OA and healthy subjects.132 However, another recent publication showed that, in the MDX mouse
model of Duchenne muscular dystrophy, the deletion of Lcn2,
either genetically or blocking its activity with a monoclonal antibody, prevented or reverted bone loss induced by this disease.135
Despite the lack of new evidence on this topic, a study showed
that, as in OA cartilage, in IVVD LCN2 can form a complex with
MMP9, preventing its degradation and promoting its catabolic
role. Lcn2 expression and MMP9 activity were also upregulated
by nerve growth factor in annulus fibrosus (AF) cells, promoting
the degeneration of AF tissue in vivo.136
In a study comparing patients with SLE with healthy controls,
no significant difference was found in serum LCN2 levels.137
However, a recent study proposed cerebrospinal fluid LCN2 as
a reliable biomarker of neuropsychiatric SLE.138
In a mouse model, Lin et al. found that serum LCN2 levels
were significantly higher in the ank/ank model than in the wild
type used as control and those levels in the ankylosis model were
positively correlated with disease score. In addition, circulating
LCN2 levels were modulated by PPARc, which might be a potential pathway involved in inflammation and ankylosis in AS. More
studies are needed to elucidate the mechanism of action of
PPARc regulating Lcn2 expression.139
Chemerin
Chemerin has been proposed as a link between RA disease activity and treatment response, mediating at the same time chronic
inflammation and obesity. Plasma chemerin levels decreased
after weight loss, improving RA state in overweight or obese
patients.140 Vazquez-Villegas et al. reported higher serum chemerin levels in patients with RA with functional disability compared with patients with RA without a disability.104 In a recent
study evaluating serum chemerin as a biomarker of RA disease
activity, patients with RA with and without diabetes mellitus
showed no differences in serum chemerin levels. A positive correlation was detected between serum chemerin levels and clinical
variables such as DAS-28-CRP, serum CRP levels, and swollen
joint count. Chemerin levels in patients with moderate or severe
RA activity (DAS > 2.9) were higher than those with RA in remission/mild disease activity (DAS < 2.9). Patients with RA and high
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chemerin levels (103 ng/ml) were shown to have a higher risk
of moderate or severe disease activity.141 Recently, it was shown
that the serum chemerin levels of patients with RA increased
after 6 months of TNFa inhibition, but decreased after 1 year of
anti-TNF therapy.142
Chemerin levels observed in synovial fluid and membrane were
higher in patients with OA than in patients with non-OA joint diseases. In addition, these levels were positively correlated with disease severity.143 Another study also confirmed this positive
correlation, although no association was found between serum
chemerin levels and OA severity.144 A cohort study reported that
patients with hip, knee, or hand primary OA presented higher
serum chemerin levels compared with healthy individuals,
although they did not show significant associations with the radiologically diagnosed severity of the disease.145 In an in vitro study,
chondrocyte cells stimulated with chemerin reduced the proliferative capacity, presenting a synergism with IL1b stimulation.
Assessing gene expression, both treatments were confirmed to
cause downregulation of MMP1, MMP3, MMP13, and all protective genes in OA. This study also found that phosphorylation of
Akt/Erk pathway was involved in the signaling.146
Muruganandan et al. investigated the mechanism involved in
MSC adipogenic and osteoblastogenic differentiation mediated
by chemokine-like receptor 1 (CMKLR1) signaling. They demonstrated that chemerin/CMKLR1 modulates canonical Wnt signaling in MSCs and that CMKLR1 is a Wnt-responsive gene that
causes a negative feedback loop to restrain osteoblastogenic Wnt
signaling. They also proved Notch signaling involvement in this
process.147 It has also been shown that the chemerin receptor is
expressed in osteoclasts, and that its protein expression is higher
in mature osteoclasts compared with preosteoclasts. In addition,
the authors showed that chemerin enlarges the functional resorption capacity of osteoclasts and that ERK5 activation is involved in
chemerin regulation of osteoclast activity.148 A study assessing the
role of another chemerin receptor, GRP1, in bone metabolism
showed that GPR1 deficiency caused severe osteoporosis associated with lower sex hormones in serum in male mice.149 Finally,
Li et al. reported that chemerin in bone marrow promotes osteogenic differentiation and bone formation in vitro and in vivo
through Akt/Gsk3b/b-catenin signaling activation.150
In a recent publication assessing this topic, Hu et al. showed
that levels of the expression of chemerin and its receptor
CMKLR1 in NP tissue were markedly increased with a higher
degeneration grade. They also observed that the expression levels
were lower in AF tissue. The authors reported a positive correlation of serum chemerin levels with lipid metabolism and higher
chemerin levels in an obese group versus a control group. The
same study showed that chemerin can reduce collagen II, aggrecan, and SOX9 expression, and promote the expression of
MMP9, MMP13, and ADAMTS5, resulting in inhibition of ECM
synthesis, enhancement of its degradation, and disruption of
the ECM synthesis balance. They also found that NF-jB and
upstream AKT phosphorylation and TLR4 and CMKLR1 receptors were involved in chemerin signaling in NP cells. Finally,
Hu et al. showed that in vivo chemerin overexpression increased
the loss of disc height, enhancing IVDD progression.151 Chougule et al. showed no significant differences in serum chemerin
levels between patients with SLE and healthy controls.78
The role of chemerin in AS has not yet been elucidated. In a
study assessing the link between adipokines and radiographic
spinal progression in patients with AS, no differences were
observed in serum chemerin levels during the spinal progression
stages.32
Adipsin
Adipsin is an adipogenesis marker gene in adipocyte differentiation of BM-MSCs and is secreted by adipocytes, promoting their
differentiation.152
Adipsin serum levels did not show significant differences
between patients with early stages of RA and healthy subjects.153
In patients with RA with comorbid type 2 diabetes mellitus, a significant reduction in adipsin serum levels was observed after
6 months of IL1-blocking agent administration, whereas no
change was detected in patients treated with a TNF inhibitor.154
Adipsin is secreted from the IPFP, which has previously been
implicated in OA pathogenesis. It has also been used as a MetS
serum marker in patients with OA and is recognized to be implicated in joint tissue homeostasis.155–156 A study found that IPFP
expression of adipsin is suppressed by moderate exercise, which
appears to be mediated by CITED2, a mechanosensitive transcriptional regulator with chondroprotective activity that might have
a role in the modulation of adipsin and other adipokines secreted
from the IPFP.157 In patients with OA, serum and cartilage adipsin
levels were higher compared with non-OA controls. A recent
study evaluated a group of adipokines and inflammatory factors
and their serum ratios in patients with OA classified according
to their BMI. An increase in the adipsin/MCP1 ratio in obese subjects was only associated with lateral compartment knee cartilage
volume loss over time. This might indicate that, in patients with a
higher BMI, adipsin have a predominant role in lateral compartment cartilage loss above that reported for other potential factors.144 An exploratory study also found that leptin levels and
systemic inflammation were positively correlated with higher
adipsin levels.158 Further analysis confirmed that higher baseline
values of adipsin in serum were associated with greater cartilage
volume loss in the lateral compartment in an OA population at
a mild to moderate stage of the disease.159 Adipsin levels were significantly higher in the serum and synovial fluid of patients with
OA. Both synovial membranes and chondrocytes expressed high
levels of adipsin, although its expression in synoviocytes, especially in osteoblasts, was low.159 Using a mouse model,
Valverde-Franco et al. demonstrated the in vivo role of adipsin in
OA as a contributing factor to knee tissue degradation. They
observed that the alterations in cartilage and synovial membrane
were significantly reduced in the absence of adipsin. They
reported that adipsin might be involved in the pathophysiology
of OA by activating the alternative complement pathway. This
study showed that adipsin expression in human OA synovial
membrane and cartilage is higher than controls. By contrast,
adipsin expression levels in joint cells were similar in both OA
and control.159 Recently, a study characterized adipsin serum
levels from patients with knee OA as CRP-related metabolic
inflammation and positively associated it with the symptoms,
but not with knee structural changes.120
In a recently published study on postmenopausal women, no
differences were observed in median circulating adipsin levels
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between the low BMD group and the control group.160 Another
study reported significantly higher serum levels of adipsin in
postmenopausal women with low BMD compared with women
with normal BMD. They also found that adipsin circulatory
levels were not affected by the patient age, but were affected by
years since menopause.121
As with other adipokines, adipsin contributes to low-grade
inflammatory response in autoimmune diseases such as SLE,
although its pathophysiology is not yet clear. Chougule et al.
reported significantly elevated serum adipsin levels in patients
with nontreated SLE compared with healthy controls, although
no correlation was found with disease activity. They also
reported that adipsin serum levels were significantly higher in
patients with SLE with renal involvement compared with those
without renal involvement.78
To the date, no research has been published regarding the role
of adipsin in IVDD and AS.(See Figs. 1-5).
Apelin
Apelin is a peptide that binds specifically to the angiotensin
domain type 1 receptor-associated proteins (APJs), which belong
to the G-protein-coupled receptor family.161 This apelin/APJ system is present around the body.162 The lack of apelin could suppress the Wnt/b-catenin pathway, which is the principal reason
why apelin is correlated with osteoporosis. In addition, the lack
of apelin decreases lysyl oxidase (LOXL)-3 and LOXL4 expression,163 which participate in collagen fiber production, and have
an impact on osteoblast formation. Apelin is related to the procollagen 1 N-terminal propeptide (P1NP) and C-terminal
telopeptide of type I collagen (ICTP). Recent studies showed that
apelin is positively correlation with PINP, but negatively with
ICTP.164
Drug Discovery Today
FIGURE 2
Schematic of the principal actions of adiponectin in bone and synovia.
Adiponectin leads to cartilage and synovia inflammation by increasing nitric
oxide synthase 2 (NOS2), interleukin (IL)-6, IL8, and metalloproteinases. It
also contributes to bone erosion, decreasing its mineralization and
increasing its degradation. For additional defintions, please see the main
text.
Apelin has been identified as a predicting indicator for arthritis.
Recent studies described how apelin stimulates IL1b expression
Drug Discovery Today
FIGURE 1
Schematic of the role of leptin in the musculoskeletal diseases. On the one hand, leptin can induce disc degradation by increasing protease and nitric oxide
(NO) secretion, which contributes to intervertebral disc degeneration (IVDD). On the other hand, leptin reduces chondrocyte autophagy, induces chondrocyte
senescence, increases reactive oxygen species (ROS) production and migration of immune cells, and leads to cartilage degradation and inflammation. For
additional defintions, please see the main text.
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FIGURE 3
Schematic of the action of visfatin action in different tissues in osteoarthritis (OA) and rheumatoid arthritis (RA). Visfatin levels increase in degraded cartilage
and increase with disease stage, stimulating the secretion of inflammatory signals. For additional defintions, please see the main text.
Drug Discovery Today
FIGURE 4
Schematic of the role of resistin in osteoarthritis (OA) and rheumatoid arthritis (RA). Resistin can induce synovial fibroblast vascular cell adhesion molecule 1
(VCAM1) upregulation and chemokine overexpression by fibroblast-like synoviocyte (FLS) and macrophage-like interleukin (IL)-1b and tumor necrosis factor
(TNF)-a, promoting monocyte adhesion and inflammation.
via PI3K and ERK.165 Both apelin and IL1b have roles in OA as
proinflammatory mediators, which explains how this peptide is
involved in disease progression. Nevertheless, apelin levels in
patients with RA were lower than in healthy controls.166 Apelin
is a determining element in OA progression, increasing the mRNA
expression of several metalloproteinases, such as MMP1, MMP3,
and MMP9, and IL1b in vitro.167 By contrast, intra-articular injection of apelin decreased levels of type II collagen, ADAMTS4 and
ADAMTS5.167–168 Some studies have reported higher levels of apelin in patients with OA than in healthy controls.168
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Drug Discovery Today
FIGURE 5
Schematic of the role of chemerin in bone. Chemerin decreases osteoblast generation, induces osteoclast differentiation, and induces bone degeneration. It
also contributes to disk degradation by reducing the synthesis of matrix proteins and inducing the synthesis of metalloproteinases.
Vaspin
Vaspin is a protein excreted by WAT with an important role in
metabolic diseases, such as obesity or diabetes.169 This adipokine
was identified for the first time in the visceral adipose tissue of
the type 2 diabetes model Otsuka Long–Evans Tokushima Fatty
rat, being part of the serpin family, explaining why it is also
called serpinA12.170
Vaspin protein and gene expression were first detected in visceral adipose tissue, and were notably higher in obese patients.
This expression, observed in cartilage, synovium, meniscus, IPFP,
and osteophytes, suggests that vaspin is involved in pathways
related to OA.171 Higher serum levels of vaspin we re detected
in patients with RA compared with controls.172 There is also evidence that levels of vaspin are higher in RA than OA in the synovial fluid.173
Vaspin has been reported to prevent osteoclastogenesis in
RAW 264.7 cells by inhibiting nuclear factor of activated T cell
c1 expression.174 Some data showed how serum levels of vaspin
and BMD in femoral neck and hip are positively correlated in
postmenopausal women.175 There is also a downregulation of
the vaspin mRNA levels in PBMCs in patients with SLE, which
suggests that this adipokine is important in disease progression,
although more studies are required to confirm this.176
Progranulin
Progranulin (PGRN) is a glycoprotein of 593 amino acids
encoded by GRN. It was first identified as a growth factor in
1990, and has since been found to be involved in many biological and pathological processes, including inflammation, cancer,
immunity, and diabetes, among others. It is secreted by several
cell types, such as adipocytes, chondrocytes, macrophages, and
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skeletal muscle cells. Full-length PGRN has 7.5 granulin
domains, which can be released individually via proteolytic
cleavage by many enzymes.177 PGRN binds to the TNF receptors
TNFR1 and TNFR2, thus interfering with TNFa-mediated inflammatory signaling pathways.178 It also binds to death receptor 3
(DR3), which is involved in various inflammatory processes,
inhibiting its binding to its only known ligand, TL1A.179 In addition, PGRN induces the proliferation of Tregs and the production
of the anti-inflammatory cytokine IL10 via FOXO4–STAT3.180
Many studies have confirmed the anti-inflammatory role of
PGRN in RA and OA. PGRN levels in serum and synovial fluids
of patients with RA were higher than in healthy controls.181–182
Moreover, the PGRN/TNFa ratio was correlated to the stage of
the disease. Recently, serum PGRN levels have been suggested
as a promising indicator of postoperative disease activity in
patients with RA who underwent orthopedic surgery.183 In
patients with OA, the expression of PGRN protein and mRNA
was increased in cartilage, synovial, and IPFP tissue samples.184
In addition to its anti-inflammatory action, PGRN showed a
chondroprotective role in OA by promoting the anabolism of
chondrocytes mainly through the TNFR2/AKT pathway.185
Similar to RA and OA, the PGRN levels in patients with SLE were
significantly higher and correlated with disease activity,78,186
although its role in the disease progression remains
controversial.187
The previously mentioned susceptibility of PGRN to proteolytic cleavage hinders its use as a therapeutic agent. The individually released granulins are believed to be proinflammatory and
can counteract the anti-inflammatory action of full-length
PGRN. The granulin domains F, A, and C, as well as the adjacent
linker region, were identified as domains involved in binding
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What’s new?
Meteorin-like protein
Meteorin-like (Metrnl) (also known as IL41) is a novel cytokine
expressed by activated macrophages and barrier tissues.192
Although some cytokines, such as TNFa, IL17a, IL12, and IL4,
induce the production of Metrnl by bone marrow macrophages,
others, such as IFNc and TGFb, inhibit that production.
The levels of Metrnl in circulation were reported to be related
to in vivo inflammatory responses.192 Over the past few years, it
became clear that Metrnl is associated with some human diseases
in addition to being overexpressed in psoriasis and RA. These
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with TNF receptors. This information gave rise to the development of atsttrin, a more stable PGRN-derived engineered molecule comprising half units of granulins F, A,and C, in addition
to the linker region.188 Atsttrin binds specifically to TNF receptors and was proved to be even more potent in terms of its
anti-inflammatory effects than PGRN itself.179,189 It was also
reported to have a protective role in OA,177 bone regeneration
activity,190 and, more recently, as a therapeutic agent for IVDD
in mice.191 Despite these promising data, there is a lack of
research around atsttrin, with no reported clinical trials as yet.
(See Table 1-6).
TABLE 1
Recent studies involving adipokines in OA.
Protein
Model of study
Conclusion
Refs
Leptin
Human serum
OA chondrocytes
Human serum
Synovial fluid
OA sinoviocytes
OA synovial fibroblast
Human synovia
RNA from cartilage
Human cartilage
Increased in patients with knee OA
High doses induce cell senescence mediated by mTOR pathway
Higher in patients with OA and increase with clinical stage
Correlates with severity and local inflammation in knee OA in women
MiRNA might mediate oxidative stress produced by NF-jB induction by visfatin and resistin
Promotes IL-6 and TNFa production by the inhibition of miR199a-5p expression
Induces ICAM-1 expression and monocyte adhesion by inhibiting miR-320a
Increases matrix mineralization and reduces collagen type I expression
Promotes degradation of hip OA cartilage proteoglycan and induces production of
proinflammatory cytokines (IL-6, MCP-1, CCL20, and CCL4) and MMPs
Correlates with knee OA progression and inflammation state
Correlates with OA; affects VCAM-1 expression and monocyte adhesion in human OASFs by
inhibiting miR-381
Enhances expression of TNF-a and IL-1b in OASFs by inhibiting miR-149 expression
Overexpression and knockout do not affect OA pathogenesis
Synovial fluid and synovial membrane levels higher in patients with OA
13
Correlated with knee, hip, and wrist OA
Significantly enhances phosphorylation of AKT/ERK in chondrocytes
Levels positively correlated with cartilage destruction
Serum and synovia levels correlated with cartilage degradation
145
Leptin and resistin
Adiponectin
Visfatin and resistin
Visfatin
Resistin
LCN2
Chemerin
Adipsin
Human serum
Human serum and
OASFs
Mouse
Human serum and
synovial fluid
Human serum
OA rat chondrocytes
Human serum
Human serum,
synovia, and cartilage
200
14
54
99
100
101
93
102
117
118
119
133
114
146
144
159
TABLE 2
Recent studies involving adipokines in RA.
Protein
Model of study
Conclusion
Refs
Leptin
Leptin and resistin
RA synovial fibroblasts
Human serum
11
Leptin and vaspin
[Adi’]ponectin
Human serum
RA synovial fibroblasts
Human serum and mouse
Increases ROS expression trigger RA-FLS migration
Resistin concentrations correlate with radiographic progression; leptin promotes new bone
formation in AS
Levels increase in early RA
Inhibition of p38 MAPK or AMPK is not sufficient to inhibit adiponectin signal
Induces expression of OPN, which recruits osteoclasts and initiates bone erosion in patients
with RA
Induces a proinflammatory state in osteoblasts and osteoclasts
Circulating adiponectin levels significantly higher in patients with RA than in controls
High levels correlate with functional disability in RA
Plasma levels correlate with disease activity
Higher levels increase risk of moderate–severe disease activity in RA
Contributes to pathogenesis of RA by increasing chemokine production by FLSs via CAP1 in
synovial tissue
High levels correlated with inflammation; increases TNFa production in macrophages
104
Serum levels correlate with RA and disease activity
129
Adiponectin and
visfatin
Chemerin
Osteoclasts and osteoclasts
Human serum
Human serum
Resistin
FLS
LCN2
Human serum and
macrophages
Human serum
31
153
45
46
74
52
140
141
113
115
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TABLE 3
Recent studies involving adipokines in AS.
Protein
Model of study
Conclusion
Refs
Resistin, leptin, and adiponectin
Leptin
Leptin and resistin
Human serum
Human serum
Human serum
30
LCN2
Leptin and adiponectin
Human and mouse sera
Human serum
Only serum resistin is associated with AS development
Correlates with AS stage
Resistin concentrations correlated with radiographic progression;
leptin promotes new bone formation in AS
High levels associated with AS; PPARy agonist upregulates LCN2
Inversely correlate with radiographic progression
32
31
139
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TABLE 4
Recent studies involving adipokines in SLE.
Protein
Model of study
Conclusion
Refs
Adiponectin, adipsin, and resistin
Human serum
78
Adiponectin
Human serum
Adipsin and resistin are elevated in patients with SLE; adiponectin
correlates with disease activity
No association between adiponectin level and risk of SLE
Correlates with SLE disease activity
Leptin levels reduced in SLE and correlate negatively with disease stage;
adiponectin levels are related to SLE and disease stage
Both levels are related to SLE
Vaspin levels decrease and adiponectin levels increase in SLE
Leptin, adipsin, chemerin, and resistin
Human serum
Adiponectin and resistin
Vaspin and adiponectin
Human serum
Human PBMCs
79
124
78
126
137
TABLE 5
Recent studies involving adipokines in osteoporosis.
Protein
Model of study
Conclusion
Refs
Leptin
Rat
19
Adiponectin
Bone mesenchymal stem cell
Overexpression induces osteogenic differentiation and can stimulated periodontal
regeneration in osteoporotic conditions
Inhibits osteoclastogenesis by suppressing NF-jB and MAPK pathways
Facilitates osteogenic differentiation and osteogenesis by Wnt/b-catenin pathway
modulation
Inhibits osteoclast differentiation and proliferation of BMMs
Does not correlate with BMD
Levels do not change in patients with osteoporosis or osteoarthritis
Inhibits osteoblastogenic signals mediated by WNT pathway
Increases osteoclast activity and have crucial role in bone homeostasis
90
Promotes osteogenic differentiation and bone formation via Akt/Gsk3b/b-catenin
axis
Lower in patients with osteoporosis than in healthy patients
Correlate with BMD
150
Bone marrow-derived
monocytes
Human serum
Human serum
MSCs from rat
Mouse and bone marrow
cells from mouse
Bone marrow cells
Visfatin
LCN2
Chemerin
Apelin
Adiponectin and resistin
Human serum
Human serum
70
71
53
132
147
148
164
160
TABLE 6
Recent studies involving adipokines in IVD Degeneration.
Protein
Model of
study
Conclusion
Refs
Visfatin
Resistin
Rat model
macrophages
110
Chemerin
Human and
rat sera
Promotes IL-6 expression in NP cells via JNK/ERK/p38-MAPK signaling pathways
Increases expression of CCL4 through p38-MAPK and NF-jB signaling pathways in NP cells, causing infiltration of
macrophages
Levels higher in degenerated nucleus pulposus tissues; overexpression related to IVDD progression in rat; induces
matrix degradation by NF-jB signaling
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data suggest that Metrnl has a significant role in chronic inflammatory diseases.193
Asprosin
The novel adipokine asprosin was discovered in 2016 in a study
of Neonatal Progeroid Syndrome (NPS),194 in which patients
have a mutation of FBN1, and a lack of asprosin. This adipokine
is derived by the cleavage of profibrilin 1, encoded by the last two
exons of this protein.195 This adipokine was shown to stimulate
orexigenic agouti-related protein peptide neurons (AgRP1) and
inhibit anorexigenic neurons proopiomelanocortin (POMC),194
regulating appetite. As an experimental outcome, it was
described how recombinant asprosin induces hyperglycemia
and hyperinsulinemia.196 Recently, asprosin was described to
be localized in human cartilage, and its levels in serum to be correlated with the cartilage marker COMP upon hip replacement
surgery in patients with OA.197
Isthmin 1
Recently, reports showed that adipocytes secrete a novel protein
with insulin-like effects, called isthmin 1.198 A clear correlation
was recently found between isthmin 1 and obesity in pubertal
boys,199 suggesting isthmin 1 as a potential biomarker of obesity
in young populations. However, this association was not present
in young women, indicating a putative sexual dimorphism.199
Concluding remarks
MSDs are one of the major causes of disability around the world.
To decrease their burden and improve the quality of life of
patients, it is vital to identify novel biomarkers and new potential therapeutic targets. The dysfunction of adipose tissue, as in
obesity, has emerged as a relevant link between metabolic alterations and MSDs. Adipokines constitute a superfamily of bioactive molecules, which have been extensively studied over the
past 25 years and have a key role in MSDs. Most of these molecules have been reported to be associated with MSDs, and most
are produced by musculoskeletal cells, such as chondrocytes,
synovial cells, or bone cells, promoting a metabolic imbalance
and triggering or cooperating in amplifying an inflammatory
response. This suggests that the local production of adipokines
in the musculoskeletal system has an additional role in
immune–metabolic crosstalk. Clarifying the roles and mechanisms driving the functionality of adipokines in MSDs is crucial,
not only for understanding the pathophysiology of the diseases
themselves, but also for the identification of new therapeutic targets and the design of novel therapeutic molecules. A clear example of this approach is the identification of the binding domains
in PGRN that allow binding to TNFR2, which gave rise to the
engineering of atsttrin, a more stable and specific PGRNderived molecule with promising anti-inflammatory, chondroprotective, and bone regenerative properties.177
It is challenging to fully identify the contribution of each adipokine in the pathogenesis of inflammatory, metabolic, and
immuno-associated diseases because most adipokines show wide
range of functionalities across different tissues and cell types.
Hence, there are only a few approved pharmacologically active
molecules with adipokines as therapeutic targets. Some of these
molecules are primarily aimed at targeting adipokine receptors,
such as the recombinant methionyl human leptin (metreleptin)
and leptin itself, whereas other drugs have been repurposed as
regulators or modulators of adipokine secretion, as in the case
of thiazolidinediones and metformin. In terms of leptin, probably the a are nearing a clearest view as chondrodestructive role
in OA, which could lead to potential avenues for a leptin-based
therapy. For instance, the control of circulating leptin levels, as
well as local joint levels, by means of soluble, high-affinity
leptin-binding molecules, analogous to anti-TNFa biologicals
used to treat RA, might be a feasible option. Another conceivable
recourse might be the block of leptin receptors with specific
monoclonal humanized antibodies or mutant leptins that are
capable of binding to leptin receptors without activating them.
It is clear that these molecules should be designed to avoid the
block of leptin receptors in the central nervous system, which
could induce obesity and hyperphagia. Nevertheless, new
advances in drug bioengineering and drug delivery (e.g., the
use of biodegradable injectable hydrogels) would suggest that
such local therapy is possible. Therefore, it will be vital to better
characterize the pathophysiological role of adipokines in preclinical models of musculoskeletal degenerative-inflammatory diseases. Unfortunately, data from preclinical studies are scarce
and support no conclusions as yet.
Therefore, it is of great interest to evaluate these molecules in
MSDs in which adipokines are involved. In addition, as more
information about the roles of adipokines in MSDs becomes
available, these molecules are likely to be crucial for the development of novel pharmacological approaches to immune-inflam
matory-degenerative MSDs.
Data availability
No data was used for the research described in the article.
Acknowledgments
This work was supported by Xunta de Galicia (Servizo Galego de
Saude, SERGAS), through a research-staff contract (ISCIII/SERGAS) to O.G, which is SERGAS Staff Personnel (I3SNS stable
Researchers). Instituto de Salud Carlos III (ISCIII) and FEDER
funded through a predoctoral research scholar to C.R-F.
(Exp.18/00188). M.G-R. is a recipient of predoctoral contract
funded by Xunta de Galicia (IN606A-2020/010). A.C.B. is a recipient of a predoctoral contract funded by Secretaría de Estado de
Universidades, Investigación, Desarrollo e Innovación, Ministerio de Universidades (FPU2018- 04165). Y.F is a ‘Sara Borrell’
researcher funded by ISCIII and FEDER [CD21/00042]. O.G. is
member of Red de Inflamación e Inmunopatología de Órganos
y Sistemas - Enfermedades Inflamatorias [RD21/ 0002/0025] via
ISCIII and FEDER. ISCIII and FEDER also supports O.G. and J.P.
[ PI20/00902]. The work of O.G. was also supported by Research
Executive Agency of the European Union in the framework of
MSCA-RISE Action of the H2020 Program [Project number
734899], and Xunta de Galicia, Consellería de Educación,
Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN) [GPC IN607B2019/10]. We
would like to acknowledge Dr. Miguel-Angel González-Gay, Dr.
Antonio Mera, Dr. Francisca Lago, Dr. Maurizio Capuozzo, and
www.drugdiscoverytoday.com
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Miss Mariam Farrag for their help and valuable discussions during the writing of this article.
Drug Discovery Today
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Volume 27, Number 11
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November 2022
Declaration of interests.
The authors declare no conflict of interest.
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