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Osteoclasts—Key Players in Skeletal Health and Disease

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  • Authors: Deborah Veis Novack1,2, Gabriel Mbalaviele3
  • Editor: Siamon Gordon4
    Affiliations: 1: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine; 2: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; 3: Musculoskeletal Research Center, Division of Bone and Mineral Diseases, Department of Medicine; 4: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec June 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0011-2015
  • Received 15 May 2015 Accepted 30 September 2015 Published 10 June 2016
  • Deborah Veis Novack, [email protected]; Gabriel Mbalaviele, [email protected]
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  • Abstract:

    The differentiation of osteoclasts (OCs) from early myeloid progenitors is a tightly regulated process that is modulated by a variety of mediators present in the bone microenvironment. Once generated, the function of mature OCs depends on cytoskeletal features controlled by an αβ-containing complex at the bone-apposed membrane and the secretion of protons and acid-protease cathepsin K. OCs also have important interactions with other cells in the bone microenvironment, including osteoblasts and immune cells. Dysregulation of OC differentiation and/or function can cause bone pathology. In fact, many components of OC differentiation and activation have been targeted therapeutically with great success. However, questions remain about the identity and plasticity of OC precursors and the interplay between essential networks that control OC fate. In this review, we summarize the key principles of OC biology and highlight recently uncovered mechanisms regulating OC development and function in homeostatic and disease states.

  • Citation: Novack D, Mbalaviele G. 2016. Osteoclasts—Key Players in Skeletal Health and Disease. Microbiol Spectrum 4(3):MCHD-0011-2015. doi:10.1128/microbiolspec.MCHD-0011-2015.


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The differentiation of osteoclasts (OCs) from early myeloid progenitors is a tightly regulated process that is modulated by a variety of mediators present in the bone microenvironment. Once generated, the function of mature OCs depends on cytoskeletal features controlled by an αβ-containing complex at the bone-apposed membrane and the secretion of protons and acid-protease cathepsin K. OCs also have important interactions with other cells in the bone microenvironment, including osteoblasts and immune cells. Dysregulation of OC differentiation and/or function can cause bone pathology. In fact, many components of OC differentiation and activation have been targeted therapeutically with great success. However, questions remain about the identity and plasticity of OC precursors and the interplay between essential networks that control OC fate. In this review, we summarize the key principles of OC biology and highlight recently uncovered mechanisms regulating OC development and function in homeostatic and disease states.

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A model of OC differentiation. OCs differentiate from HSCs. The hematopoietic niche comprises endothelial cells and perivascular stromal cells, which exhibit mesenchymal stem cell (MSC) features. It is still unclear whether OC precursors directly differentiate into OCs or enter the bloodstream before reentering the bone microenvironment to form OCs. In any scenario, higher levels of chemoattractants toward bone surfaces, including bone ECM proteins, lipid mediators (e.g., sphingosine-1-phosphate), and ECM degradation products, create gradients that attract OC precursors to the hard tissue, where they fuse and complete the differentiation process. Conversely, higher levels of perivascular chemorepellents (not drawn for simplicity) may also contribute to the migration of OC precursors toward the endosteum.

Source: microbiolspec June 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0011-2015
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Key molecules involved in OC function. Loss of function of any of the depicted molecules causes osteopetrosis due to defective OC activity. OCs adhere to bone matrix proteins via integrin αβ and are polarized such that the plasma membrane-facing bone is convoluted (ruffled) and contains the proton pump (v-ATPase) and Cl channel 7 (ClC7), whereas the basolateral membrane bears the HCO /Cl antiporter. Cytoplasmic carbonic anhydrase type II (CAII) generates the protons to be secreted into the resorption lacuna beneath the cell. This lacuna becomes isolated from the rest of the extracellular space by the tight adhesion of αβ to the bone surface at the sealing zone. The cytoplasmic domain of β recruits signaling proteins, which induce the association of actin with interacting partners (including talin, vinculin, kindlin, myosin IIA, and paxillin) and formation of an actin ring that defines the periphery of the ruffled membrane. Concerted action of ClC7 and v-ATPase produces a high concentration of HCl that acidifies the resorption lacuna, leading to the dissolution of the inorganic components of the bone matrix. Acidified cytoplasmic vesicles containing lysosomal enzymes such as cathepsin K (Cat K) are also transported toward the bone-apposed plasma membrane and, ultimately, the sealed resorption lacuna, where they digest the exposed matrix proteins.

Source: microbiolspec June 2016 vol. 4 no. 3 doi:10.1128/microbiolspec.MCHD-0011-2015
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