From trans

• Basic structure and function of bone

  • Composed of 206 bones
  • 12% of body weight
  • Mechanical support, force transmission, internal organ protection, and mineral homeostasis
  • Major site of hematopoiesis during postnatal life
• Matrix

  Extracellular component of bone
• Composition of matrix

  • Osteoid (35%)
  • Minerals (65%)
• Mineral

  Hydroxyapatite Ca10(PO4)6(OH)2 - gives bone its hardness and serves as repository for 99% of calcium and 85% of phosphorus in the body
• Osteoid


  Consist of Type 1 collagen and glycosaminoglycans, and other proteins
• Osteopontin (osteocalcin)


  Produced by osteoblasts and contributes to regulation of bone formation, mineralization, calcium homeostasis
• Serum osteopontin


  Specific marker of osteoblast activity
• Bone maturation & metabolism is sensitive to cytokines and growth factors
• Bone matrix types


  • Woven
  • Lamellar
• Woven bone

  Produced rapidly e.g. during fetal development or fracture repair, less structural integrity due to haphazard arrangement of collagen fibers, always abnormal in adult
• Lamellar bone


  Parallel arrangement of collagen fibers
• Cellular components of bone

  • Osteoblasts
  • Osteocytes
  • Osteoclasts
• Osteoblasts


  On surface of osteoid matrix, synthesize, transport, and assemble matrix and regulate mineralization. Quiescent osteoblasts remain on trabecular surface or become embedded within the matrix as osteocytes.
• Osteocytes

  Interconnected by dendritic cytoplasmic processes through tunnels (canaliculi) within the matrix. Help control calcium and phosphate levels in microenvironment, detect mechanical forces, and translate them into biologic activity - MECHANOTRANSDUCTION
• Osteoclasts


  Specialized multinucleated macrophages, derived from monocytes and resorb bone
• Developmental disorders of bone & cartilage

  • Defects in nuclear proteins and transcription factors
  • Defects in hormones and signal transduction proteins
  • Defects in extracellular structural proteins
  • Defects in metabolic pathways (enzyme, ion channels, and transporters)
• Homeobox proteins defect

  Disorganized mesenchymal condensation, and differentiation of osteoblasts and chondrocytes -> abnormal bone development
• Brachydactyly type D and E

  • Homeobox HOXD13 gene, shortening of terminal phalanges of the thumb and big toe
• Loss of function mutation in RUNX2

  Results in cleidocranial dysplasia, autosomal dominant with patent fontanelles, delayed closure of cranial sutures, wormian bones, delayed eruption of secondary teeth, primitive clavicles, short stature
• Achondroplasia


  Most common skeletal dysplasia, major cause of dwarfism, autosomal dominant, gain of function mutation in FGFR3 gene, 90% stem from new mutations in paternal allele, FGF mediated FGFR3 activation normally inhibits endochondral growth, exaggerated by FGFR3 gain of function mutation, retarded cartilage growth, shortened proximal extremities, enlarged head with bulging forehead, depression of the root of the nose, trunk normal length, not associated with changes in longevity, intelligence or reproductive status
• Thanatophoric dysplasia


  Most common lethal form of dwarfism, FGFR3 gain of function mutation, disproportionately short (micromelic) limbs, frontal bossing, relative macrocephaly, small chest cavity, bell-shaped abdomen, results in respiratory insufficiency -> frequently die at birth or soon after, decreased chondrocyte proliferation and disorganization within the zone of proliferation
• Defects in extracellular structural proteins

  • Mutations in the major bone and cartilage collagens (Type I, II, IX, X, XI)
  • Give rise to highly variable presentations ranging from lethal disease to premature osteoarthritis
• Osteogenesis imperfecta

  Brittle bone disease, most common inherited disorder of connective tissue, deficiency in type I collagen synthesis, affects bone and tissues rich in type I collagen (joints, eyes, ears, skin, and teeth), caused by replacement of glycine residue within triple-helical domain with another amino acid, fundamental abnormality is too little bone -> extreme skeletal fragility, blue sclerae, hearing loss, dental imperfections, decreased synthesis of qualitatively normal collagen associated with mild skeletal abnormalities, type 2 variant is fatal in utero or during perinatal period with extraordinary bone fragility and multiple intrauterine fractures
• Osteopetrosis

  Reduced bone resorption due to deficient osteoclast development or function -> diffuse, symmetric skeletal sclerosis, bones are stonelike, brittle and fracture easily, first genetic bone disease treated with hematopoietic stem cell transplantation
• Albers-Schonberg disease

  Mild autosomal dominant form of osteopetrosis, CLCN7 mutation encodes for proton-chloride exchanger on osteoclast surface, required for pit acidification
• Other genetic causes of osteopetrosis

  • TCIRG1 mutation (autosomal recessive, encodes a subunit of osteoclast vacuolar H+ATPase that is necessary for acidification of resorption pit)
  • CA2 (Carbonic Anhydrase 2) mutation (autosomal recessive, CA2 facilitates resorption pit acidification by osteoclasts and urinary acidification by RTE cells, accompanied by renal tubular acidosis)
  • IKBKG mutation (X-linked, encodes NEMO regulatory subunit of inhibitor of kappaB kinase IKK complex that is involved in NF-kB activation, cause of osteopetrosis that is not due to defective acidification)
• Mucopolysaccharidoses


  Lysosomal storage diseases, acid hydrolase deficiency, acid hydrolase degrades dermatan sulfate, heparan sulfate, and keratan sulfate, extracellular mucopolysaccharide accumulate within chondrocytes and induce apoptosis, extracellular mucopolysaccharide accumulation leads to structural defects in articular cartilage, skeletal manifestations result from abnormalities in the cartilage anlage, growth plates, costal cartilages, and articular surfaces, affected individuals are frequently of short stature and have chest wall abnormalities and malformed bones
• Osteopenia

  Decreased bone mass, 1 to 2.5 SD below the mean
• Osteoporosis


  Defined as osteopenia that is severe enough to significantly increase the risk of fracture, bone mass at least 2.5 SD below mean peak bone mass in young adults, may be localized or involve the entire skeleton
• Causes of osteoporosis

  • Age-related changes (reduced proliferative and biosynthetic capacity, diminished ability to make bone)
  • Reduced physical activity (increases rate of bone loss)
  • Genetic factors (RANK, RANKL, and OPG encode key osteoclast regulators, HLA and estrogen receptor gene)
  • Calcium nutritional state (calcium deficiency reduces peak bone mass, relative deficiencies of calcium and Vitamin D and elevated PTH levels)
  • Hormonal influences (estrogen deficiency plays a major role, increases inflammatory cytokines IL6, TNF, IL1 that stimulate osteoclast recruitment and activity)
• Osteomalacia and rickets


  Manifestations of impaired mineralization of bone matrix, vs. osteoporosis - normal mineralization of bone and bone mass decreased, due to abnormal vitamin D metabolism or deficiency, rickets is the disorder in children that interferes with bone deposition in growth plate, osteomalacia is the adult form where bone formed during remodeling is undermineralized and predisposed to fractures
• Hyperparathyroidism

  Increases bone resorption, PTH activates osteoclasts directly and indirectly by increasing RANKL expression on osteoblasts, increases calcium resorption by renal tubules, increases urinary phosphate excretion, increases synthesis of active vitamin D to enhance intestinal calcium absorption and mobilize bone calcium, elevated PTH is responsible for bone changes in primary hyperparathyroidism, in chronic renal insufficiency can lead to secondary hyperparathyroidism
• Osteitis fibrosa cystica


  Uncommon, combination of increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors, hallmark of severe hyperparathyroidism (von Recklinghausen disease of bone)
• Renal osteodystrophy


  Collective skeletal changes that occur in chronic renal disease, including those associated with dialysis, can manifest as osteopenia/osteoporosis, osteomalacia, secondary hyperparathyroidism, and growth retardation
• Secondary hemorrhage


  Macrophage recruitment and ingrowth of reparative fibrous tissue to create a mass lesion called brown tumor
• Brown tumor

  The brown color reflects vascularity, hemorrhage, and hemosiderin deposition
• Cystic degeneration of brown tumors is common
• Generalized osteitis fibrosa cystica (von Recklinghausen disease of bone)


  The combination of increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of severe hyperparathyroidism
• Renal osteodystrophy


  Describes the collective skeletal changes that occur in chronic renal disease, including those associated with dialysis
• Manifestations of renal osteodystrophy

  • Osteopenia/osteoporosis
  • Osteomalacia
  • Secondary hyperparathyroidism
  • Growth retardation