Bones

• Bone functions


  • Mechanical support
  • Force transmission
  • Internal organ protection
  • Mineral homeostasis
  • Major site of hematopoiesis during postnatal life

  
• Bone matrix


  Extracellular component of the bone, composed of osteoid (35%) and minerals (65%)

  
• Osteoid


  Consists of type I collagen and smaller amounts of glycosaminoglycans and other proteins

  
• Osteopontin


  Protein produced by osteoblasts that contributes to the regulation of bone formation, mineralization, and calcium homeostasis

  
• Woven bone


  • Produced rapidly (e.g., during fetal development or fracture repair), but the haphazard arrangement of collagen fibers imparts less structural integrity than the parallel collagen fibers of lamellar bone
  • Always abnormal in adults, but is not specific for any particular disease

  
• Lamellar bone


  • Parallel collagen fibers impart more structural integrity than woven bone

  
• Cellular components of bone

  • Osteoblasts
  • Osteocytes
  • Osteoclasts

  
• Osteoblasts


  On the surface of the osteoid matrix, synthesize, transport, and assemble matrix and regulate mineralization

  
• Osteocytes


  Interconnected by an intricate network of dendritic cytoplasmic processes through tunnels (canaliculi) within the matrix, help control Ca and phosphate levels in the microenvironment, detect mechanical forces, and translate those forces into biologic activity called mechanotransduction

  
• Osteoclasts


  Specialized multinucleated macrophages derived from circulating monocytes that resorb bone

  
• Endochondral ossification


  1. Cartilage mold (anlagen) synthesized by mesenchymal precursor cells

  2. Central medullary canal created by chondroblasts

  3. Osteoblasts deposit cortex beneath nascent periosteum

  4. Endochondral ossification forms secondary centers of ossification at longitudinal ends (epiphysis)

  5. Chondrocytes within growth plates undergo sequential proliferation, hypertrophy, and apoptosis

  6. Matrix mineralizes during apoptosis and is invaded by capillaries, providing nutrients for osteoblast activation and osteoid synthesis

  7. Calcified cartilage matrix resorbed leaving primary spongiosa, the earliest bone trabeculae

  
• Intramembranous ossification


  1. Dense layer of mesenchyme directly ossified by osteoblasts without a cartilage anlagen

  2. Bones enlarge by deposition of new bone on a preexisting surface (appositional growth)

  
• Factors regulating bone development

  • Growth hormone
  • Thyroid hormone
  • Indian hedgehog
  • Parathyroid hormone
  • Wnt growth factors
  • SOX9
  • RUNX2
  • Fibroblasts growth factors
  • Bone morphogenic proteins

  
• Bone remodeling


  Continuous process that turns over approximately 10% of the skeleton each year, repairs damage, and may change the shape of bones in response to mechanical forces

  
• Basic multicellular unit (BMU)

  Unit of coupled osteoblast and osteoclast activity on the bone surface, where osteoclast attachment, bone resorption, osteoblast attachment and proliferation, and matrix synthesis occur sequentially

  
• Developmental anomalies can result from localized disruption of the migration and condensation of mesenchyme (dysostosis) or global disorganization of bone and/or cartilage (dysplasia)

  
• Dysostoses


  Defects in mesenchymal condensation and differentiation into cartilage anlage, including complete absence of a bone or digit (aplasia), extra bones or digits (supernumerary digit), and abnormal fusion of bones (syndactyly, craniosynostosis)

  
• Dysplasias


  Arise from mutations in genes that control the development or remodeling of the entire skeleton
• Dysostoses


  • Brachydactyly types D and E
  • Cleidocranial dysplasia

  
• Brachydactyly types D and E


  Caused by mutations in the homeobox HOXD13 gene, characterized by shortening of the terminal phalanges of the thumb and big toe, respectively

  
• Cleidocranial dysplasia


  Autosomal dominant disorder caused by loss-of-function mutations in RUNX2, characterized by patent fontanelles, delayed closure of cranial sutures, Wormian bones, delayed eruption of secondary teeth, primitive clavicles, and short stature

  
• Achondroplasia


  Most common skeletal dysplasia and major cause of dwarfism, autosomal dominant disorder caused by gain-of-function mutations in the FGF receptor (FGFR3) gene, results in shortened proximal extremities, enlarged head with bulging forehead, and depression of the root of the nose despite a trunk of relatively normal length

  
• Thanatophoric dysplasia


  Most common lethal form of dwarfism, caused by FGFR3 gain-of-function mutations distinct from those that cause achondroplasia, affects ~1 in every 20,000 live births, results in disproportionately short (micromelic) limbs, frontal bossing, relative macrocephaly, small chest cavity, and bell-shaped abdomen, leads to respiratory insufficiency and frequent death at birth or soon after
• Mutations in major bone and cartilage collagens (types I, II, IX, X, and XI) give rise to highly variable presentations ranging from lethal disease to premature osteoarthritis

  
• Osteogenesis imperfecta (OI)


  Most common inherited disorder of connective tissue, phenotypically heterogenous disorder caused by deficiencies in type I collagen synthesis, principally affects bone but also impacts other tissues rich in type I collagen like the joints, eyes, ears, skin, and teeth

  
• Osteogenesis imperfecta


  Caused by mutations in genes encoding the a1 and a2 chains of type I collagen, replacement of a glycine residue within the triple-helical domain with another amino acid results in misfolding of collagen polypeptides and defective assembly of higher-order collagen chains, mutant collagens also interfere with assembly of wild-type collagen chains (dominant negative effect)
• Osteogenesis imperfecta


  • Fundamental abnormality is too little bone resulting in extreme skeletal fragility
  • Other findings include blue sclerae, hearing loss, and dental imperfections secondary to dentin deficiency

  
• Osteopetrosis


  Also known as "marble bone disease", rare genetic diseases characterized by reduced bone resorption due to deficient osteoclast development or function, leading to diffuse, symmetric skeletal sclerosis

  
• Mutations underlying osteopetrosis


  Interfere with acidification of the osteoclast resorption pit, which is required for the dissolution of calcium hydroxyapatite within the matrix

  
• Osteopetrosis


  • Albers-Schönberg disease (autosomal dominant form caused by CLCN7 mutation)
  • Autosomal recessive osteopetrosis (caused by TCIRG1 mutation)

  
• Mucopolysaccharidoses


  Lysosomal storage diseases where mucopolysaccharides accumulate within chondrocytes and induce apoptosis, extracellular mucopolysaccharide accumulation leads to structural defects in articular cartilage, resulting in many skeletal manifestations
• Mucopolysaccharidoses


  • Lysosomal storage diseases
  • Mucopolysaccharides accumulate within chondrocytes and induce apoptosis
  • Extracellular mucopolysaccharide accumulation leads to structural defects in articular cartilage
• Affected individuals are frequently of short stature and have chest wall abnormalities and malformed bones

  
• Osteopenia


  Decreased bone mass

  
• Osteoporosis


  Osteopenia that is severe enough to significantly increase the risk of fracture

  
• Radiographically, osteoporosis is considered bone mass at least 2.5 standard deviations below mean peak bone mass in young adults. Osteopenia is 1 to 2.5 standard deviations below the mean

  
• Peak bone mass


  • Achieved during young adulthood
  • Magnitude determined largely by hereditary factors, especially polymorphisms in the genes that influence bone metabolism
  • Physical activity, muscle strength, diet, and hormonal state also make important contributions

  
• Once maximal skeletal mass is attained, bone resorption slightly exceeds formation, resulting in age-related bone loss that averages 0.7% per year

  
• The most common forms of osteoporosis are senile and postmenopausal

  
• Age-related changes in osteoporosis

  • Reduced proliferative and biosynthetic capacity, and attenuated response to growth factors of osteoblasts, resulting in a diminished ability to make bone
  • Reduced physical activity increases the rate of bone loss