Bone

• consists of type I collagen and smaller amounts of glycosaminoglycans and other proteins. One of these proteins, osteopontin (also called osteocalcin), is produced by osteoblasts and contributes to the regulation of bone formation, mineralization, and calcium homeostasis.

  osteoid
• Serum _ levels are used as a specific marker of osteoblast activity. Bone maturation and metabolism are also sensitive to cytokines and growth factors and are thus regulated by diverse inputs, which include locally and systemically produced factors, as well as mechanical force.

  osteopontin
• Bone matrix can be _ or _

  woven or lamellar
• is produced rapidly (e.g., during fetal development or fracture repair), and is abnormal in adults

  woven bone
• Long bones are composed of a dense outer cortex and a central medulla. The latter is supported by bony trabeculae interspersed with marrow, which may be fatty (white) or hematopoietic (red).

  lamellarbone
• on the surface of the osteoid matrix synthesize, transport, and assemble matrix and regulate mineralization. Osteoblast activity is tightly regulated by hormonal and local mediators. Quiescent osteoblasts, which can be recognized by a decrease in cytoplasmic volume, may remain on the trabecular surface or become embedded within the matrix as osteocytes.


  osteoblasts
• are interconnected by an intricate network of dendritic cytoplasmic processes through tunnels (canaliculi) within the matrix. _ help control calcium and phosphate levels in the microenvironment, detect mechanical forces, and translate those forces into biologic activity—a process called mechanotransduction.


  osteocytes
• are specialized multinucleated macrophages that are derived from circulating monocytes and resorb bone. Surface integrin proteins allow osteoclasts to attach to the matrix and create a sealed extracellular trench (resorption pit). proteases, predominantly matrix metalloproteases (MMPs), into the pit results in dissolution of inorganic and organic bone components.

  osteoclasts
• Most bones that form during embryogenesis develop from a cartilage mold via __

  endochondral ossification
• The cartilage mold (anlagen) is synthesized by mesenchymal precursor cells. A central medullary canal within the anlagen is created by chondroblasts at approximately _ weeks of gestation.

  8
• _ begin to deposit the cortex beneath the nascent periosteum of the midshaft (diaphysis). This forms a primary center of ossification resulting in radial bone growth.


  osteoblasts
• At the longitudinal ends (epiphysis), endochondral ossification forms _ centers of ossification. Eventually, plates of cartilage anlage become entrapped between the expanding centers of ossification forming physes or growth plates


  secondary
• Flat bones, for example the cranium, are formed by __, in which a dense layer of mesenchyme is directly ossified by osteoblasts without a cartilage anlagen.

  intramembranous ossification
• Bones enlarge by deposition of new bone on a preexisting surface, a process called __

  appositional growth
• secreted by the anterior pituitary gland induces and maintains chondrocyte proliferation.

  growth hormone
• secreted by the thyroid gland acts on proliferating chondrocytes to induce hypertrophy.

  thyroid hormone
• is secreted locally by prehypertrophic chondrocytes and coordinates chondrocyte proliferation and differentiation with osteoblast proliferation.

  indian hedgehog
• produced by perichondrial stromal cells and early proliferating chondrocytes activates the PTH receptor to maintain chondrocyte proliferation.

  parathyroid hormone
• _ growth factors are expressed in the growth plate– proliferating zone and, via Frizzled and LRP5/6 receptors, activate β-catenin to promote chondrocyte proliferation and maturation

  wnt
• _ is a transcription factor expressed by proliferating, but not hypertrophic, chondrocytes that is essential for differentiation of chondrocyte precursors.

  SOX9
• is a transcription factor expressed in early hypertrophic chondrocytes and immature mesenchymal cells that controls terminal chondrocyte and osteoblast differentiation.

  RUNX2
• are secreted by a variety of mesenchymal cells. FGFs (most notably FGF-3) act on hypertrophic chondrocytes to inhibit proliferation and promote differentiation.

  fibroblast growth factor
• members of the TGF-β family, are expressed at various stages of chondrocyte development and have diverse effects on chondrocyte proliferation and hypertrophy at the growth plate.

  bone morphogenic protein
• The adult skeleton appears static but actually undergoes continuous change via a tightly regulated process known as _.

  remodeling
• Remodeling occurs within the bone ___(BMU), which consists of a unit of coupled osteoblast and osteoclast activity on the bone surface. Osteoclast attachment, bone resorption, osteoblast attachment and proliferation, and, finally, matrix synthesis occur sequentially at the BMU.

  basic multicellular unit
• Events at the BMU are regulated by cell-to-cell interactions and cytokines, and several signaling pathways- 3 factors: Osteoclast, osteoblast, prevents interaction of RANKL to RANK

  RANK, RANKL, osteoprotegerin
• When stimulated by _, RANK signaling activates NF-κB, which is essential for the generation and survival of osteoclasts.

  RANKL
• A second important pathway involves ___, a factor produced by osteoblasts that is also crucial for the generation of osteoclasts.

  macrophage colony-stimulating factor (M-CSF)
• _ proteins produced by osteoprogenitor cells bind to LRP5 and LRP6 on osteoblasts to activate β-catenin signaling and osteoprotogerin (OPG) synthesis

  WNT
• _ prevents bone resorption by inhibiting osteoclast differentiation.

  OPG
• Conversely, osteocytes produce _, which inhibits WNT/β-catenin signaling and promotes bone formation. The importance of these pathways is emphasized by rare germline mutations in OPG, RANK, RANKL, LRP5, and _ genes, which severely disrupt bone metabolism and produce congenital bone disorders

  sclerostin
• The balance between bone formation and resorption is modulated by _and_ signaling

  RANK and WNT
• Another level of control involves paracrine signaling between osteoblasts and osteoclasts. Matrix breakdown by osteoclasts liberates and activates growth factors, cytokines, and enzymes _, some of which stimulate osteoblasts. Thus, substances that initiate bone deposition are released into the microenvironment during bone resorption

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

  dysostosis
• _ may occur in isolation or as part of more complex syndromes, and are caused by defects in mesenchymal condensation and differentiation into cartilage anlage. The most common forms include complete absence of a bone or entire digit (aplasia), extra bones or digits (supernumerary digit), and abnormal fusion of bones (e.g., syndactyly, craniosynostosis).

  Dysostose
• _ arise from mutations in genes that control development or remodeling of the entire skeleton. It is important to note that while the term _ in this context implies abnormal growth, it is not a precursor of neoplasia, as is the case with dysplasias of epithelial cells

  dysplasia
• HOXD13 Transcription factor Short, broad terminal phalanges of first digits

  Brachydactyly types D and E

  A)

  B)

  C)

  D)

  E)

  F)

  G)

  H)

  I)

  J)

  K)

  L)
• SOX9 Transcription factor Sex reversal, abnormal skeletal development

  Camptomelic dysplasia
• RUNX2 Transcription factor Abnormal clavicles, Wormian bones, supernumerary teeth

  Cleidocranial dysplasia
• TBX5 Transcription factor Congenital abnormalities, forelimb anomalies

  Holt-Oram syndrome