Pathology Ch 26 1206-1220
Bones – Osteonecrosis
-Bones have a role in mineral homeostasis, houses hematopoietic elements, supports body
-bones largely made of organic matrix (osteoid) and mineral calcium hydroxyapatite (hardness)
-Osteoprogenitor cells – pluripotent mesenchymal stem cells found in all bony surfaces, and
differentiate into osteoblasts regulated by factors RUNX2/CBFA1 and WNT/B-catenins
-Osteoblasts and Lining Cells –located on surface of bones and can synthesize/transport and
arrange proteins of matrix, and initiate process of mineralization
-have receptors that bind PTH, vitamin D, leptin, and estrogen, and in turn regulate
differentiation and function of osteoclasts
-osteoblasts surrounded by organic matrix become osteocytes, and on outside are lining cells
-Osteocytes – communicate with each other and with cells on bony surface via cytoplasmic
processes that traverse tunnels in matrix known as canaliculi
-osteocytes help control Ca/PO4 levels and detect mechanical forces
-Osteoclasts – responsible for bone resorption, derived from hematopoietic progenitors that
also give rise to monocytes and macrophages
-factors influencing osteoclast differentiation include M-CSF, IL-1, TNF
-osteoclasts bind to bone surface through integrins where they form a resorption pit, and the
cell membrane overlying the resorption pit is a ruffled border (numerous folds) for surface area
-osteoclast removes mineral by generating acidic environment utilizing a proton pump system
and digests organic component by releasing proteases
-All of the cells work together to regulate bone homeostasis through several pathways: one
involves 3 factors:
1. transmembrane RANK receptor (for NF-kB) expressed on osteocyte precursors
2. RANK ligand (RANKL) – expressed on osteoblasts and marrow stromal cells
3. Osteoprotegrin (OPG) – secreted decoy receptor made by osteoblasts that binds RANKL and
short-circuits its interaction with RANK
-when RANKL binds RANK, it activates NF-kB which generates osteoclasts
-a SECOND pathway involves M-CSF produced by osteoblastsand M-CSF receptor expressed by
osteoclast progenitors
-M-CSF stimulates tyrosine kinase activation critical for generation of osteoclasts
-THIRD pathway is WNT/B-catenin, where WNT produced by marrow stromal cells bind to
LRP5/6 receptors on osteoblasts to trigger activation of B-catenin and production of OPG
-bone formation and resorption are tightly coupled, such as OPG and RANKL oppose one
another, and bone resorption/formation can be tipped by altering RANKL:OPG ratio
-systemic factors influencing their expression include PTH, estrogen, testosterone,
glucocorticoids, vitamin D, inflammatory cytokines, growth factors
-another level of control involves paracrine crosstalk between osteoblasts and osteoclasts,
where osteoblasts can inhibit or enhance osteoclast development/function by expressing OPG
and RANKL
-as osteoclasts break bone down, matrix enzymes are liberated with stimulate osteoblasts, so as
bone is broken down to its elemental units, substances are released into microenvironment that
initiate its renewal
-proteins of bone include type 1 collagen and many noncollagenous proteins derived from
osteoblasts; osteoblasts deposit collagen in a random weave (woven bone), or in an ordered,
layered manner known as lamellar bone. Woven bone is in sites of rapid bone formation such
as fetal skeleton and base of growth plates; produced quickly and resists forces equally from all
directions
-presence of woven bone in adult is ALWAYS abnormal, but not characteristic of disease
-Lamellar bone gradually replaces woven bone during growth is deposited slowly and is stronger
-Osteocalcin is measurable in serum and is a marker for osteoblasts
-osteocytes, osteoblasts, and osteoclasts work together in a basic multicellular unit
-as skeleton grows early in life (modeling), bone formation predominates. Later it remodels
-peak bone mass occurs in early adulthood, determined by SNPs in vitamin D, LRP5/6, nutrition,
physical activity, age, and hormonal status
Bone Growth and Development – skeletal development dependent on homeobox genes; most
bones formed as cartilage model and harden through endochondral ossification, where
cartilage is removed by osteoclast-type cells forming the medullary canal, while osteoblasts line
periosteum in midshaft and deposit the beginnings of cortex, known as primary center for
ossification
-similar sequence occurs in the epiphysis, known as secondary center of ossifications
-cartilage becomes entrapped between the two centers of ossification: growth plate
-chondrocytes in the growth plate are responsible for longitudinal growth through FGF , BMP,
hedgehog, and PTH signaling
-regions of apoptosis have matrix remineralizing and resorbed by osteoclasts, though remnant
struts persist and act for scaffolding for deposition of bone, called primary spongiosa or bony
trabeculae
-intramembranous formation forms cranium and lateral clavicles, are formed by osteoblasts
directly from a fibrous layer of tissue derived from mesenchyme, and enlargement of bone is
through deposition of new bone on preexisting surface: appositional growth
Developmental Abnormalities in Bone cells, Matrix, and Structure – frequently genetically
based
-Dysostoses – anomaly resulting from localized problem in migration of mesenchymal cells and
formation of condensations, limited to embryologic structures and may be due to SNPs in HOX
-Dysplasias – mutations in regulators of skeletal organogenesis (signaling molecules), collagens,
that affect cartilage and bone tissues globally
Malformations and Diseases Caused by Defects in Nuclear Proteins and Transcription Factors –
simplest is failure of a bone to develop, formation of extra bones, or syndactyly. Some result
from defects in formation of mesenchymal condensations and their differentiation into cartilage
and are caused by defects in HOX genes and cytokines
-mutation HOXD13 gene produces an extra
-loss of function in RUNX2 results cleodocranial dysplasia, causing patent fontanelles, delayed
closure of sutures, Wormian bones, delayed secondary teeth, primitive clavicles + short height
Diseases Caused by Defects in Hormones and Signal Transduction Mechanisms
-Achondroplasia (dwarfism) – most common disease of growth plate and cause of dwarfism –
mutation in FGF receptor 3 (FGFR3). Normally FGF action on FGFR3 INHIBITS cartilage
proliferation; and mutations cause constitutive activation of FGFR3 to suppress growth
-autosomal dominant disorder and 80% arise from new mutations on paternal allele
-Thanatophoric Dwarfism – lethal form of dwarfism, caused of gain-of-function mutations in
FGFR3 differing from achondoplasia; micromelic shortening of limbs, underdeveloped chest
cavity causes respiratory insufficiency
-Increased bone mass caused by gain of function mutations in LPR5, a receptor that activates
WNT/B-catenin pathway in osteoblasts. These diseases: endosteal hyperostosis, Van Buchem
disease, and autosomal dominant osteopetrosis type 1, are characterized by increased bone
mass
-loss of function mutations in LPR5 cause osteoporosis pseudoglioma syndrome
Type 1 Collagen Diseases (Osteogenesis Imperfecta (OI)) – brittle bone disease, characterized
by deficiencies in collagen type 1 synthesis affecting bone, joints, eyes, ears, skin, teeth
-results from mutations in genes that encode the α1 and α2 chains of collagen
-mutations resulting in decreased synthesis associated with MILK skeletal abnormalities
-severe/lethal mutations have abnormal polypeptide chains cannot be arranged in triple helix
-mutations in cartilage-associated protein (CRTAP) and (LEPRE1) are involved in this disease
-Osteogenesis imperfecta is separated into 4 subtypes:
1. OI Type 1 – compatible with survival, decreased α1-chain synthesis; childhood fractures, blue
sclera, hearing loss, dental imperfections, little bone
2. OI Type 2 – fatal in-utero, bone fragility and multiple intrauterine fractures, unstable triple
helix due to abnormal α1 or 2 chain
3. OI Type 3 – Progressive/deforming, altered structure, growth retardation, fractures
4. OI Type 4 – compatible with survival, short a2 chain, postnatal fractures
Diseases associated with mutations of Types 2, 9, 10, and 11 collagen
-these are important structural components of hyaline cartilage; severe type 2 collagen
disorders are where it is not secreted by chondrocytes and insufficient bone formation occurs.
Milder disorders show reduced synthesis of normal type 2 collagen
Diseases associated with defects in folding and degradation of macromolecules –
Mucopolysaccharidoses – group of lysosomal storage diseases caused by deficiencies in the
enzymes that degrade dermatan sulfate, heparan sulfate, and keratan sulfate; chondrocytes
normally metabolizes extracellular matrix mucopolysaccharides , and cartilage formation is
affected
-skeletal manisfestastions of mucopolysaccharidoses result from abnormalities of hyaline
cartilage
Diseases Associated with Defects in Metabolic Pathways (enzymes, ion channels, transporters)
Osteopetrosis – marble bone disease and Albers-Schönberg disease characterized by reduced
bone resorption and diffuse symmetric skeletal sclerosis due to impaired osteoclast function
-bones are stonelike but brittle and fracture easily
Pathogenesis of Osteopetrosis – most mutations interfere with process of acidification of
osteoclast resorption pit, required for dissolution of hydroxyapatite within matrix
-examples include defects in gene CA2, encoding carbonic anhydrase II which is required by
osteoclasts to generate protons from CO2 and H2O.
-absence of this enzyme prevents osteoclasts from acidifying the resorption pit and solubilizing
hydroxyapatite
-in an autosomal recessive form, mutation in chloride channel CLCN7 interferes with H+ ATPase
pump in osteoclast ruffled border
-another mutation is in TCIRG1 encoding component of proton pump
-less severe disorder is mutation in RANKL, causing fewer osteoclasts
Morphology of Osteopetrosis – deficient osteoclast activity where bone lacks a medullary canal,
ends of long bones are bulbous. Neural foramina are small and compress nerves, primary
spongiosa is normally removed but persists leaving no room for hematopoietic marrow
-deposited bone is not remodeled and tends to be woven, causing brittleness
Clinical Features of Osteopetrosis – fracture, anemia, and hydrocephaly are often seen, cranial
nerve defects and infections
-osteopetrosis was first genetic disease treated with bone marrow transplantation
Diseases associated with decreased bone mass
Osteoporosis – characterized by porous bones and reduced bone mass; predispose to fracture
-may be localized to one limb or entire skeleton as manifestation of metabolic bone disease
-often referred to senile and postmenopausal, leading to vulnerability to fractures
Pathogenesis – peak bone mass achieved during young adulthood. Once maximal skeletal mass
is attained, small deficit in bone formation accrues with every resorption and formation cycle
(0.7% per year)
-age related changes – osteoblasts in elderly people have reduced proliferative and biosynthetic
ability than from younger people (diminished capacity to make bone). This is called senile
osteoporosis, categorized as low-turnover variant
-reduced physical activity – increases rate of bone loss, as exercise influences bone density
-Genetic Factors – top associated genes are RANKL, OPG, RANK, MHC, estrogen receptor
-Calcium nutritional state – deficient calcium intake, particularly in girls during rapid bone
growth, stunts peak bone mass achieved
-Hormonal Influences – women may lose up to 35-50% of bone after menopause, and
postmenopausla osteoporosis is characterized by hormone-dependent acceleration of bone
loss; estrogen plays major role through action of cytokines
-decreased estrogen  increased inflammatory cytokine secretion by monocytes and bone
marrow cells which stimulate osteoclast recruitment and activity by increasing levels of RANKL
and diminishing OPG
Morphology of Osteoporosis – entire skeleton is affected in both major osteoporotic diseases
-in postmenopausal, increase in osteoclast activity affects mainly bones that have increased
surface area like vertebral bodies, and trabecular plates become perforated
-in senile osteoporosis, cortex is thinned by subperiosteal and endosteal resorption and
haversian systems are widened
Diseases Caused by Osteoclast Dysfunction
Paget Disease (Osteitis Deformans) – divided into 3 phases:
initial osteolytic stage
mixed osteoclastic-osteoblastic stage, ends with osteoblasts predominating
burnt-out quiescent osteosclerotic phase
-net effect is gain in bone mass; begins in late adulthood (70y.o) and more common after
Pathogenesis of Paget Disease – mutations in SQSTM1 are present in 50% of familial cases
-SQSTM mutations enhance NF-kB activation by RANK signaling, leading to increased osteoclast
activity and an increased susceptibility to disease
-first suggested as an inflammatory condition possibly due to paramyxovirus
Morphology of Paget – hallmark is mosaic pattern of lamellar bone, like a jigsaw puzzle shows
prominent cement lines
-initial lytic phase there are waves of osteoclastic and numerous resorption pits, osteoclasts
large with 10-12 nuclei, and osteoclasts persist In mixed phase, but bone surfaces primarily lined
with osteoblasts
-marrow adjacent is replaced with loose connective tissue containing osteoprogenitor cells and
numerous blood vessels
-new bone may be woven or lamellar, but usually all remodeled to lamellar; bone later becomes
larger than normal and composed of coarsely thickened trabeculae and corticies
-axial skeleton or proximal femur involved in 80% of cases
-pain localized to affected bone is common and caused by microfractures or by bone
overgrowth that compresses nerve roots
-enlargement of craniofacial skeleton may produce leontiasis ossea and heavy head
-weight bearing causes anterior bowing of femurs and tibia and distorts femoral heads,
resulting in development of severe secondary osteoarthritis
-chalkstick-type fractures are frequent complication and occur in long bones of lower
extremities
-hypervascularity of pagetic bone warms overlying skin and increased blood flow can act like
arteriovenous shunt leading to high-output heart failure
-variety of tumor and tumor-like conditions develop in pagetic bone; benign lesions
include giant-cell tumor, granuloma; complication can be sarcoma
Diseases associated with Abnormal Mineral Homeostasis –
Rickets and Osteomalacia – characterized by matrix demineralization most often related to lack
of vitamin D or its metabolism; rickets is a children’s disorders where deranged bone growth
causes skeletal deformities, and in adults is called osteomalacia for failure of mineralization
during remodeling process
Hyperparathyroidism – classified into primary and secondary types; primary results from
autonomous hyperplasia or tumor, where secondary is caused by prolonged hypocalcemia
resulting in compensatory hypersecretion of PTH
-PTH detected by osteoblasts, which release factors to stimulate osteoclast activity
-entire skeleton is affected, anatomic changes known as osteitis fibrosa cystica is rarely
encountered
-secondary hyperparathyroidism is not as severe as primary
Morphology of hyperparathyroidism – increased osteoclast activity affects cortical bone
(subperiosteal, osteonal, and endosteal) more than cancellous bone
-in cancellous bone, osteoclasts tunnel into and dissect centrally along length of trabecular
creating appearance of railroad tracks and producing dissecting osteitis, decreased bone density
or osteopenia
-bone loss predisposes to microfractures and secondary hemorrhages that elicit influx of
macrophages and ingrowth of reparative fibrous tissue, known as brown tumor, brown due to
vascularity, hemorrhage, and hemosiderin
-combined picture of increased bone cell activity, peritrabecular fibrosis, and cystic brown
tumors are hallmarks called generalized osteitis fibrosa cystica (Von Recklinghausen disease)
-decrease in bone mass predisposes to fractures, deformities, and joint pain
Renal Osteodystrophy – skeletal changes of chronic renal disease, including (1) increased
osteoclastic bone resorption mimicking osteitis fibrosa cystica (2) delayed matrix mineralization,
(3) osteosclerosis, (4) growth retardation, (5) osteoporosis
-histologic bone changes with end-stage renal failure can be divided into 3 major disorders:
1. high-turnover osteodystrophy – increased bone resorption/formation with more
resorption
2. low turnover or aplastic disease – manifested by adynamic bone (little
osteoclast/osteoblast activity)
3. osteomalacia
Pathogenesis – chronic renal failure results in phosphate retention and hyperphosphatemia
-hyperphosphatemia induces secondary hyperparathyroidism; PO4 regulates PTH secretion
-hypocalcemia develops as levels of vitamin D (1,25OHD3) fall because of decreased conversion
of 25-OHD3 to active form by damaged kidneys, inhibition of renal hydroxylase, and reduced
intestinal absorption calcium due to low 1,25 OH2D3 levels
-PTH secretion increases all levels of serum calcium. 1,25 D3 suppresses PTH expression and
secretion; in renal failure there is a decrease in binding of 1,25 D3 to parathyroid cells and
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
hydroxyapatite from matrix
-Aluminum deposition has iatrogenic origin, and interferes with Ca-hydroxyapatite and results in
osteomalacia. Aluminum is not only toxic to bone but also has been implicated as cause of
dialysis encephalopathy and microcytic anemia with chronic renal failure
Fractures – fractures are classified as either complete or incomplete; closed (simple) when the
overlying tissue is intact; compound when fracture site communicates with skin surface;
comminuted when bone is splintered; displaced when ends of bone are not aligned
-if bone breaks in a bone already affected by pathologic process: pathologic fracture
-stress fracture – slowly developing fracture that follows period of increased physical activity in
which bone is subjected to new repetitive loads
-bone can repair itself using lots of regulated genes
1.
immediately after fracture, rupture of blood vessels results in hematoma filling fracture
gap and surrounding bone injury; clotted blood provides fibrin mesh to seal fracture site and
creates a framework for influx of inflammatory cells which release PDGF, TGF-B, FGF, IL’s to
activate osteoprogenitor cells and stimulate osteoclastic/osteoblastic activity
2.
after 1 week, tissue is modulated for future matrix production and fractured ends of
bone are remodeled; this uncalcified tissue is called soft-tissue callus or procallus to provide
anchorage between fractured bones but offers no structural integrity
3.
osteoprogenitor cells deposit subperiosteal trabeculae of woven bone oriented
perpendicular to cortical axis and within medullary cavity
-cartilage forms along the fracture line and undergoes endochondral ossification forming a
network of bone that connects to reactive trabeculae deposited elsewhere in medullary cavity
-fractured ends are bridged by a bony callus
-if a nonunion allows too much motion along fracture gap, callus undergoes cystic degeneration
and the luminal surface can actually become lined with synovial cells, creating a false joint or
pseudoarthrosis
-infection is an obstacle to healing