path 1206 to 1220
Bones
 Bones largely made up of organic matrix (osteoid) and mineral calcium hydroxyapatite (gives bone strength and
hardness)
 Osteoprogenitor cells – pluripotent mesenchymal stem cells found in vicinity of all bony surfaces; RUNX2/CFA1
transcription factor network and WNT/β-catenin signaling pathway govern differentiation into osteoblasts
 Osteoblasts and lining cells located on surface of bones; synthesize, transport, and arrange proteins of matrix
and initiate process of mineralization
o Osteoblasts have receptors that bind regulatory hormones (PTH, vitamin D, leptin, and estrogen),
cytokines, growth factors, and ECM proteins; express several factors that regulate differentiation and
function of osteoclasts
o If osteoblasts either become surrounded by newly deposited organic matrix (becoming osteocytes) or
remain on bone surface and become flattened quiescent bone lining cells
 Osteocytes communicate with each other and cells on bone surface via cytoplasmic processes (canaliculi)
o Help control Ca2+ and HPO42- levels in microenvironment
o Detect mechanical forces and translate them into biologic activity (mechanotransduction)
 Osteoclasts – responsible for bone resorption; derived from same hematopoietic progenitor cells as monocytes
and macrophages
o Cytokines and growth factors that regulate osteoclast differentiation and maturation include M-CSF, IL1, and TNF
o Mature multinucleated osteoclasts form from fusion of circulating mononuclear precursors and have
limited life span
o Bind bone surface via integrins, where they form underlying resorption pit (self-contained extracellular
space like secondary lysosome)
o PM overlying resorption pit thrown into numerous folds (ruffled border), increasing surface area while
adjacent cell surface forms tight seal with bone that prevents leakage of digestion products
o Removes mineral by generating acidic environment utilizing proton pump system and digests organic
component by releasing proteases
 RANK – receptor activator for NF-κB; expressed on osteoclast precursors; binds RANKL (expressed on osteoblasts
and marrow stromal cells)
o When stimulated by RANKL, RANK signaling activates NF-κB, which is essential for generation and
survival of osteoclasts
 OPG – secreted decoy receptor made by osteoblasts and several other types of cells that can bind RANKL and
short-circuit its interaction with RANK
 M-CSF produced by osteoblasts; M-CSF receptor expressed by osteoclast progenitors; activation of receptor
stimulates tyrosine kinase activity crucial for generation of osteoclasts
 WNT proteins produced by marrow stromal cells bind to LRP5 and LRP6 receptors on osteoblasts, triggering
activation of β-catenin and production of OPG
 Paracrine crosstalk between osteoblasts and osteoclasts can control bone formation/resorption
 Osteoblasts can enhance or inhibit osteoclast development and function by expressing OPG and RANKL in
various proportions
 As osteoclasts disassemble matrix proteins deposited by osteoblasts, growth factors, cytokines, and enzymes
(such as collagenase) bound to matrix liberated and activated, including some that stimulate osteoblasts
 Proteins of bone include type 1 collagen and non-collagenous proteins derived mainly from osteoblasts
o Osteoblasts deposit collagen in either random weave (woven bone) or in orderly layered manner
(lamellar bone)
o Woven bone seen in sites of rapid bone formation (fetal skeleton and base of growth plates); produced
quickly and resists forces equally in all directions; presence in adult always abnormal, but not diagnostic
of particular disease
o Lamellar bone gradually replaces woven bone during growth; deposited much more slowly and stronger
than woven bone
o Non-collagenous proteins bound to matrix and grouped according to function; only osteocalcin unique
to bone (measurable in serum and used as marker for osteoblast activity)
Bone Modeling, Remodeling, and Peak Bone Mass
 Local collections of osteocytes, osteoblasts, and osteoclasts work together to control bone formation and
resorption, creating functional unit referred to as basic multicellular unit (BMU)
 Once skeleton reaches maturity, breakdown and renewal of bone that constitutes skeletal maintenance is
remodeling and initiates at sites experiencing fatigue and microdamage
o In adults BMUs remodel or replace 10% of skeleton annually
 Peak bone mass achieved in early adulthood after cessation of growth; determined by polymorphisms in
receptors of vitamin D and LRP5/6, nutrition, physical activity, age, and hormonal status
 Beginning in 4th decade, amount of bone resorbed by BMUs exceeds that formed, so there is steady decrement
in skeletal mass
Bone Growth and Development
 Skeletal morphogenesis determined by homeobox genes, which encode transcription factors essential for
normal development of skeleton; most bones first formed as cartilage model or anlage
 Around 8th week of gestation, endochondral ossification begins; cartilage removed by osteoclast-type cells
forming medullary canal along length of bone while concurrently, periosteum in midshaft generates osteoblasts
that deposit beginnings of cortex (primary center of ossification)
o Similar events happen in epiphysis, resulting in removal of cartilage and deposition of bone in
centrifugal fashion (secondary center of ossification) such that plate of cartilage anlage becomes
entrapped between expanding centers of ossification, forming physis (growth plate)
 Chondrocytes within growth plate responsible for longitudinal growth as they undergo proliferation, growth,
maturation, and apoptosis controlled by FGF receptors, bone morphogenic protein, hedgehog protein, and PTHrelated protein
 In region of apoptosis, matrix mineralizes and is resorbed by osteoclasts; remnant struts persist and act as
scaffolding for deposition of bone on their surfaces (primary spongiosa); first bony trabeculae
o Similar process occurs at base of articular cartilage; this is how bones increase in length and articular
surfaces increase in diameter
 Bones derived from intramembranous formation (cranium and lateral portions of clavicles) formed by
osteoblasts directly from fibrous layer of tissue derived from mesenchyme
o Enlargement of bones achieved by deposition of new bone on preexisting surface (appositional growth)
Developmental Abnormalities in Bone Cells, Matrix, and Structure
 Dysostoses – developmental anomalies resulting from localized problems in migration of mesenchymal cells and
formation of condensations; usually limited to defined embryologic structures and may result from mutations in
certain transcription factors
o Failure of bone to develop (congenital absence of phalanx, rib, or clavicle), formation of extra bones
(supernumerary ribs or digits), fusion of 2 adjacent digits (syndactylism), or development of long, spiderlike digits
o Some result from defects in formation of mesenchymal condensations and differentiation into cartilage
anlage; caused by genetic alterations that affect transcription factors (especially homeobox genes) and
certain cytokines
 Dysplasias – mutations in regulators of skeletal organogenesis, such as signaling molecules and matrix
components that affect cartilage and bone tissues globally
o Cleidocranial dysplasia – autosomal dominant disorder characterized by patent fontanelles, delayed
closure of cranial sutures, Wormian bones, delayed eruption of secondary teeth, primitive clavicles, and
short height; caused by loss of function mutation in RUNX2, which produces transcription factors
important in osteoblastogenesis and some chondrocyte cell activity
 Achondroplasia – most common growth plate disease; major cause of dwarfism; caused by mutations in FGFR3
o Normally FGF-mediated activation of FGFR3 inhibits cartilage proliferation; in achondroplasia, mutations
cause constitutive activation of FGFR3 and thereby suppress growth
o Autosomal dominant disorder; most from new mutations, almost all of which occur in paternal allele
o Shortened proximal extremities, trunk of relatively normal length, and enlarged head with bulging
forehead and conspicuous depression of root of nose
 Thanatophoric dwarfism – caused by gain-of-function mutations in FGFR3
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Affected individuals have micromelic shortening of limbs, frontal bossing, relative macrocephaly, small
chest cavity, and bell-shaped abdomen
o Underdeveloped thoracic cavity leads to respiratory insufficiency, and patients frequently die at birth or
soon after
o Diminished proliferation of chondrocytes and poor columnization in zone of proliferation in growth plate
Increased bone mass – can be caused by gain-of-function mutations in gene that encodes LPR5 (cell surface
receptor essential for activation of WNT/β-catenin pathway in osteoblasts)
o Endosteal hyperostosis, Van Buchem disease, and autosomal dominantosteopetrosis type 1
characterized by increased bone mass including cortical thickening, enlarged and elongated mandible,
and increased density and enlargement of cranial vault; can develop torus palatinus
Inactivating mutations in LPR5 cause osteoporosis pseudoglioma syndrome; skeleton severely osteoporotic
Osteogenesis imperfecta – deficiencies in synthesis of type 1 collagen; most common inherited disorder of CT
o Usually results from autosomal dominant mutations in genes that encode α1 and α2 chains of collagen
o Type II variant uniformly fatal in utero or during perinatal period
o Individuals with type I form have normal life span but experience childhood fractures that decrease in
frequency following puberty
o Blue sclerae caused by decreased collagen content, making sclera translucent and allowing partial
visualization of underlying choroid
o Hearing loss related to sensorineural deficit and impeded conduction due to abnormalities in bones of
middle and inner ear
o Dental imperfections (small, misshapen, blue-yellow teeth) secondary to deficiency in dentin
o Basic abnormality in all forms is too little bone, constituting type of osteoporosis with marked cortical
thinning and attenuation of trabeculae
Mutations in genes encoding types 2, 9, 10, and 11 collagen (important for hyaline cartilage); associated with
destruction of joints
o In severe disorders, type 2 collagen not secreted by chondrocytes; insufficient bone formation occurs
Mucopolysaccharidoses – group of lysosomal storage diseases caused by deficiencies in enzymes that degrade
dermatan sulfate, heparan sulfate, and keratan sulfate; mesenchymal cells, especially chondrocytes, normally
metabolize ECM mucopolysaccharides; hence cartilage formation severely affected
o Many skeletal manifestations result from abnormalities in hyaline cartilage
o Patients frequently short and have chest wall abnormalities and malformed bones
Osteopetrosis (marble bone disease or Albers-Schönberg disease) – group of rare genetic diseases characterized
by reduced bone resorption and diffuse symmetric skeletal sclerosis due to impaired formation or function of
osteoclasts; bones abnormally brittle and fracture easily
o Autosomal recessive is severe; autosomal dominant is mild
o Most mutations interfere with acidification of osteoclast resorption pit, which is required for dissolution
of calcium hydroxyapatite within matrix (mutations in CA2, which encodes carbonic anhydrase II)
 Carbonic anhydrase II required by osteoclasts and renal tubular cells to generate protons from
CO2 and H2O; absence of CAII prevents osteoclasts from acidifying resorption pit and solubilizing
hydroxyapatite; blocks acidification of urine by renal tubular cells
o In autosomal recessive form, mutation in Cl- channel gene (CLCN7) interferes with function of H+-ATPase
pump located on osteoclast ruffled border
o Different autosomal recessive form caused by mutation in gene TCIRG1, which encodes component of
proton pump
o Less severe autosomal recessive variant results from mutation in gene that encodes RANKL; patients
have fewer osteoclasts than normal
o Bones lack medullary canal, and ends of long bones bulbous (Erlenmeyer flask deformity) and misshapen
o Primary spongiosa (normally removed during growth) persists and fills medullary cavity, leaving no room
for hematopoietic marrow and preventing formation of mature trabeculae
o Deposited bone not remodeled and tends to be woven; intrinsic abnormalities cause bone to be brittle
and predisposed to fracture
o Severe infantile malignant osteopetrosis – autosomal recessive; fracture, anemia, and hydrocephaly,
resulting in postpartum mortality; patients who survive into infancy have CN defects and repeated
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infections because of inadequacies of marrow produced in extramedullary sites, which also causes
prominent hepatosplenomegaly
o Mild autosomal dominant benign form may not be detected until adolescence or adulthood; might have
mild cranial nerve deficits and anemia
o Treated with bone marrow transplantation since osteoclasts derived from marrow monocyte precursors
o Donor progenitor cells produce normal functioning osteoclasts, which reverse many skeletal
abnormalities
Osteoporosis – disease characterized by porous bones and reduced bone mass; predispose bone to fracture
o May be localized (as in disuse osteoporosis of limb) or involve entire skeleton (manifestation of
metabolic bone disease)
o Magnitude of peak bone mass determined largely by hereditary factors (especially polymorphisms in
genes that influence bone metabolism) physical activity, muscle strength, diet, and hormonal state
o Once max skeletal mass attained, small deficit in bone formation accrues with every resorption and
formation cycle of each basic multicellular unit
o Age-related changes in bone cells and matrix have strong impact on bone metabolism; osteoblasts from
elderly have reduced proliferative and biosynthetic potential
 Proteins bound to ECM (growth factors) lose potency over time
 Senile osteoporosis – low-turnover variant
o Reduced physical activity increases rate of bone loss because mechanical forces stimulate normal bone
remodeling; load magnitude influences bone density more than number of load cycles (weight training
more effective than jogging)
o Mutations in RANKL, OPG, and RANK predispose to osteoporosis; MHC locus mutation can cause
o Adolescent girls (not boys) tend to have insufficient calcium intake in diet; calcium deficiency occurs
during period of rapid bone growth, stunting peak bone mass ultimately achieved; greater risk for
developing osteoporosis later in life
o Calcium deficiency, increased PTH concentrations, and reduced vitamin D have role in development of
senile osteoporosis
o Postmenopausal osteoporosis characterized by hormone-dependent acceleration of bone loss that
occurs during decade after menopause; estrogen replacement protective against bone loss
 Effects of estrogen on bone mass mediated by cytokines
 Decreased estrogen levels result in increased secretion of inflammatory cytokines by blood
monocytes and bone marrow cells; cytokines stimulate osteoclast recruitment and activity by
increasing levels of RANKL while diminishing expression of OPG
 Compensatory osteoblastic activity occurs, but doesn’t keep pace, leading to high-turnover form
of osteoporosis
 Increase in osteoclast activity affects mainly bones or portions of bones with increased surface
area (cancellous compartment of vertebral bodies); trabecular plates become perforated,
thinned, and lose interconnections, leading to progressive microfractures and eventual vertebral
collapse
o Senile osteoporosis – cortex thinned by subperiosteal and endosteal resorption, and Haversian systems
widened; in severe cases, Haversian systems enlarged so cortex mimics cancellous bone; bone that
remains of normal composition
o Complications of fractures of femoral neck, pelvis, or spine (pulmonary embolism and pneumonia)
o Best procedure to accurately estimate amount of bone loss are specialized radiographic imaging
techniques (dual energy X-ray absorptiometry and quantitative computed tomography), which measure
bone density
o Prevention and treatment includes exercise, appropriate calcium and vitamin D intake, and
pharmacologic agents (bisphosphonates), which bind to bone and inhibit osteoclasts
Paget disease (osteitis deformans) – divided into 3 phases: initial osteolytic stage, mixed osteoclasticosteoblastic stage (ends with predominance of osteoblastic activity), and used-up quiescent osteosclerotic stage
o Net effect is gain in bone mass; newly formed bone disordered and architecturally unsound
o Happens in late life; genetic predisposition; mutations in SQSTM1 gene present in some cases
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SQSTM mutations enhance NF-κB activation by RANK signaling, leading to increased osteoclast
activity and increased susceptibility to disease
o Mutations in RANKL and RANK/OPG found in genetic diseases with phenotypic overlap to Paget disease
o Possible inflammatory process contribution (paramyxovirus)
o Hallmark is mosaic pattern of lamellar bone (jigsaw puzzle) produced by prominent cement lines that
anneal haphazardly oriented units of lamellar bone
o In initial lytic phase, there are waves of osteoclastic activity and numerous resorption pits; osteoclasts
abnormally large and have many more nuclei
o Osteoclasts persist in mixed phase, but many of bone surfaces lined by prominent osteoblasts; marrow
adjacent to bone-forming surface replaced by LCT that contains osteoprogenitor cells and numerous
blood vessels, which transport nutrients and catabolites to and from metabolically active sites
 Newly formed bone may be woven or lamellar
o As mosaic pattern unfolds and cell activity decreases, periosseous fibrovascular tissue recedes and is
replaced by normal marrow
o In end, bone becomes larger than normal and composed of coarsely thickened trabeculae and cortices
that are soft and porous and lack structural stability; makes bone vulnerable to deformation and stress
(fractures easily)
o Usually involves axial skeleton or proximal femur
o Pain localized to affected bone common; caused by microfractures or bone overgrowth that compresses
nerve roots
o Enlargement of craniofacial skeleton (leontiasis ossea) can cause cranium so heavy it’s hard to hold up
o Weakened pagetic bone may lead to invagination of skull base (platybasia) and compression of posterior
fossa structures
o Weight bearing causes anterior bowing of femurs and tibiae, and distorts femoral heads, resulting in
development of severe secondary osteoarthritis
o Chalkstick-type fractures usually occur in long bones of lower extremities
o Hypervascularity warms overlying skin, and in severe polyostotic disease, increased blood flow acts like
AV shunt, leading to high-output heart failure or exacerbation of underlying cardiac disease
o Can produce tumors and tumor-like conditions (giant-cell tumor, giant-cell reparative granuloma, and
extra-osseous masses of hematopoiesis)
 Sarcomas usually osteosarcoma or fibrosarcoma and arise in Paget lesions in long bones, pelvis,
skull, and spine
o Active disease has wedge-shaped lytic leading edge that may progress along length of bone
o Many patients have increased serum ALK and increased urinary excretion of hydroxyproline
o Most patients have mild symptoms that are readily suppressed by calcitonin and bisphosphonates
Rickets and osteomalacia characterized by defect in matrix mineralization, most often related to lack of vitamin
D or disturbance of its metabolism; results in osteopenia and predisposition to insufficiency fractures
Primary hyperparathyroidism results from autonomous hyperplasia or tumor, usually adenoma, of parathyroid
gland; secondary hyperparathyroidism commonly caused by prolonged states of hypocalcemia resulting in
compensatory hypersecretion of PTH
o Increased PTH detected by receptors on osteoblasts, which release factors that stimulate osteoclasts
o Anatomic changes (osteitis fibrosa cystica) rarely encountered because hyperparathyroidism usually
diagnosed and treated at early asymptomatic stage detected on routine blood tests
o Secondary hyperparathyroidism usually not as severe or prolonged as primary
o Increased osteoclast activity affects cortical bone (subperiosteal, osteonal, and endosteal surfaces) more
severely than cancellous bone
 Subperiosteal resorption produces thinned cortices and loss of lamina dura around teeth
 X-rays reveal pattern of radiolucency that is virtually diagnostic
o In cancellous bone, osteoclasts tunnel into and dissect centrally along length of trabeculae, creating
appearance of railroad tracks and producing dissecting osteitis; causes osteopenia
o Osteoblast activity also increased
o Marrow spaces around affected surfaces replaced by fibrovascular tissue
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Bone loss predisposes to microfractures and secondary hemorrhages that elicit influx of macrophages
and ingrowth of reparative fibrous tissue, creating mass of reactive tissue (brown tumor)
 Brown color result of vascularity, hemorrhage, and hemosiderin deposition; not uncommon for
lesions to undergo cystic degeneration
o Severe hyperparathyroidism also called generalized osteitis fibrosa cystica or von Recklinghausen
disease of bone
o Decrease in bone mass predisposes to fractures, deformities caused by stress of weight bearing, and
joint pain and dysfunction as lines of normal weight bearing altered
o Control of hyperparathyroidism allows bony changes to regress significantly or disappear completely
 Renal osteodystrophy – all skeletal changes of chronic renal disease, including increased osteoclastic bone
resorption mimicking osteitis fibrosa cystica, delayed matrix mineralization (osteomalacia), osteosclerosis,
growth retardation, and osteoporosis
o High-turnover osteodystrophy characterized by increased bone resorption and formation (resorption
predominates)
o Low-turnover (aplastic) disease manifested by adynamic bone (little osteoclastic or osteoblastic activity)
and less commonly osteomalacia
o Chronic renal failure results in phosphate retention and hyperphosphatemia, which induces secondary
hyperparathyroidism (phosphate regulates PTH secretion directly)
 Hypocalcemia develops as levels of vitamin D (1,25-(OH)2D3) fall because of decrease conversion
by damaged kidneys; inhibition of renal hydroxylase involved in conversion to active vitamin D
by high levels of phosphate; and reduced intestinal absorption of calcium because of low VID
 PTH secretion markedly increases at all levels of serum calcium; VID suppresses PTH gene
expression and secretion; in renal failure, there is decrease in binding of VID to parathyroid cells;
decreased degradation and excretion of PTH because of compromised renal function
 Resultant secondary hyperparathyroidism produces increased osteoclast activity
 Metabolic acidosis associated with renal failure stimulates bone resorption and release of
calcium hydroxyapatite
 DM, high dietary calcium ingestion, increasing age, and iron accumulation in bone and
aluminum deposition at site of mineralization important in genesis of adynamic renal
osteodystrophy
 Aluminum deposition can be caused by dialysis solutions and oral aluminum-containing
phosphate binders; interferes with deposition of calcium hydroxyapatite and results in
osteomalacia
 Aluminum implicated in dialysis encephalopathy and microcytic anemia in patients with
chronic renal failure
 Deposition of amyloid in bone and periarticular structures may occur in association with
hemodialysis; amyloid formed from β2-microglobulin, which is increased in blood of individuals
who undergo long-term dialysis
Fractures
 Closed (simple) fracture when overlying tissue intact
 Compound fracture when site communicates with skin surface
 Comminuted fracture – when bone splintered
 Displaced fracture – ends of bone at fracture site not aligned
 Immediately after fracture, rupture of blood vessels results in hematoma, which fills fracture gap and surrounds
area of bone injury; clotted blood provides fibrin mesh, which helps seal off fracture site and creates framework
for influx of inflammatory cells and ingrowth of fibroblasts and new capillary vessels
o Degranulated platelets and migrating inflammatory cells release PDGF, TGF-β, FGF, and interleukins,
which activate osteoprogenitor cells in periosteum, medullary cavity, and surrounding soft tissues and
stimulate osteoclastic and osteoblastic activity
o Be end of first week, hematoma organizing, adjacent tissue modulated for future matrix production, and
fractured ends of bone being remodeled (soft-tissue callus or procallus)
o Activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone oriented perpendicular
to cortical axis and within medullary cavity
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In some cases, activated mesenchymal cells in soft tissues and bone surrounding fracture line
also differentiate into chondroblasts that make fibrocartilage and hyaline cartilage
 Newly formed cartilage along fracture line undergoes endochondral ossification, forming
network of bone that connects to reactive trabeculae deposited elsewhere in medullary cavity
and beneath periosteum (bony callus)
o In early stages of callus formation, excess fibrous tissue, cartilage, and bone produced; if bones not
perfectly aligned, volume of callus greatest in concave portion of fracture site; as callus matures and
subjected to weight-bearing forces, portions that aren’t physically stressed resorbed, and callus reduced
in size until shape and outline of fractured bone reestablished
o Medullary cavity restored
Displaced and comminuted fractures frequently result in some deformity, and inadequate immobilization
permits constant movement at fracture site, so normal constituents of callus don’t form, resulting in delayed
union and nonunion
o If nonunion allows too much motion along fracture gap, central portion of callus undergoes cystic
degeneration, and luminal surface can become lined by synovial-like cells, creating false joint
(pseudoarthrosis)
Infection must be eradicated before bony union can be achieved