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Chapter 3. Osteoclast Biology and Bone Resorption

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Chapter 3. Osteoclast Biology and Bone Resorption 16 1 CHAPTER^ 66. Fuentealba LC, Eivers E, Ikeda A. Hurtado C, Kuroda H, Pera diates cooperative signaling by the transforming growth factor-p EM, De Robertis EM 2007 Integrating patterning signals: Wnti and wnt pathways. Proc Natl Acad Sci USA 97:8358-8363. GSK3 regulates the duration of the BMP/Smadl signal. Cell 71. Spinella-Jaegle S, Roman-Roman S, Faucheu C, Dunn FW, Kawai 131 : 980-993. S, Gallea S, Stiot V, Blanchet AM, Courtois B, Baron R, Rawadi 67. Sapkota G, Alarcon C, Spagnoli FM, Brivanlou AH, Massague J G 2001 Opposite effects of bone morphogenetic protein-2 and 2007 Balancing BMP signaling through integrated inputs into the transforming growth factor-pl on osteoblast differentiation. Bone Smadl linker. Mol Cell 25:441454. 29:323-330. M, M, SE, S, 72. Zhao Qiao Harris Chen D, Oyajobi BO, Mundy GR 68. Nakayama K, Tamura Y, Suzawa M, Harada S, Fukumoto Kato 2006 The zinc finger transcription factor Gli2 mediates bone mor- M, Miyazono K, Rodan GA, Takeuchi Y, Fujita T 2003 Receptor phogenetic protein 2 expression in osteoblasts in response to tyrosine kinases inhibit bone morphogenetic protein-Smad re- hedgehog signaling. Mol Cell Biol 26:6197-6208. sponsive promoter activity and differentiation of murine MC3T3- 73. Li Y, Li A, Strait K, Zhang H, Nanes MS, Weitzmann MN 2007 El osteoblast-like cells. J Bone Miner Res 18:827-835. Endogenous TNFalpha lowers maximum peak bone mass and in- 69. Hu MC, Rosenblum ND 2005 Smadl, p-catenin and Tcf4 associate hibits osteoblastic Smad activation through NF-kappaB. J Bone in a molecular complex with the Myc promoter in dysplastic renal Miner Res 22:646-655. tissue and cooperate to control Myc transcription. Development 74. Mukai T, Otsuka F, Otani H, Yamashita M, Takasugi K, Inagaki 132:215-225. K, Yamamura M, Makino H 2007 TNF-alpha inhibits BMP- 70. Labbe E, Letamendia A, Attisano L 2000 Association of Smads induced osteoblast differentiation through activating SAPKiJNK with lymphoid enhancer binding factor 1IT cell-specific factor me- signaling. Biochem Biophys Res Commun 356:1004-1010. Chapter 3. Osteoclast Biology and Bone Resorption F. Patrick Ross Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri CELL BIOLOGY OF THE OSTEOCLAST from two major sources: biochemical and genetic.(2) The unique osteoclastogenic properties of RANKL permit genera- Pathological bone loss, regardless of etiology, invariably rep- tion of pure populations of osteoclasts in culture and hence the resents an increase in the rate at which the skeleton is de- graded by osteoclasts relative to its formation by osteoblasts. performance of meaningful biochemical and molecular experi- Thus, prevention of conditions such as osteoporosis requires ments that provide insights into the molecular mechanisms by an understanding of the molecular mechanisms of bone resorp- which osteoclasts resorb bone. Further evidence has come tion. from our capacity to generate mice lacking specific genes, plus The osteoclast, the exclusive bone resorptive cell (Fig. l),is the positional cloning of genetic abnormalities in people with a member of the monocytehacrophage family and a abnormal osteoclast function. Key to the resorptive event is polykaryon that can be generated in vitro from mononuclear the capacity of the osteoclast to form a microenvironment be- phagocyte precursors resident in a number of tissues.(') There tween itself and the underlying bone matrix (Fig. 3A). This is, however, general agreement that the principal physiological compartment, which is isolated from the general extracellular osteoclast precursor is the bone marrow macrophage. Two cy- space, is acidified by an electrogenic proton pump (H+- tokines are essential and sufficient for basal osteoclastogenesis, ATPase) and a CI- channel to a pH of -4.5.(6) The acidified the first being RANKL",') and the second being macrophage- milieu mobilizes the mineralized component of bone, exposing colony stimulating factor (M-CSF), also designated CSF-1.(3' its organic matrix, consisting largely of type 1 collagen that is These two proteins, which exist as both membrane-bound and subsequently degraded by the lysosomal enzyme cathepsin K. soluble forms (the former is secreted by activated T cells),(4) The critical role that the proton pump, CI- channel, and ca- are produced by marrow stromal cells and their derivative os- thepsin K play in osteoclast action is underscored by the fact teoblasts, and thus physiological recruitment of osteoclasts that diminished function of each results in a human disease of from their mononuclear precursors requires the presence of excess bone mass, namely osteopetrosis or pyknodysosto- these nonhematopoietic, bone-residing cells."' RANKL, a sis.(2,6) Degraded protein fragments are endocytosed and member of the TNF superfamily, is the key osteoclastogenic transported in undefined vesicles to the basolateral surface of cytokine, because osteoclast formation requires its presence or the cell, where they are discharged into the surrounding intra- its priming of precursor cells. M-CSF contributes to the pro- cellular fluid.(',') It is also likely that retraction of an osteoclast liferation, survival, and differentiation of osteoclast precursors, from the resorptive pit results in release of products of diges- as well as the survival and cytoskeletal rearrangement required tion. for efficient bone resorption (Fig. 2; a brief summary of the The above model of bone degradation clearly depends on integrated signaling pathways for each osteoclastic regulator physical intimacy between the osteoclast and bone matrix, a discussed in this review is provided later in this review [Fig. 61). role provided by integrins. Integrins are a@heterodimers with The discovery of RANKL was preceded by identification of its long extracellular and single transmembrane domains.") In physiological inhibitor osteoprotegerin (OPG), to which it most instances, the integrin cytoplasmic region is relatively binds with high affinity.(') In contrast, M-CSF is a moiety long short, consisting of 40-70 amino acids. Integrins are the prin- known to regulate the broader biology of myeloid cells, includ- cipal cellhatrix attachment molecules and they mediate os- ing osteoclasts(') (see Fig. 6). teoclastibone recognition. Members of the pl family of inte- Our understanding of how osteoclasts resorb bone derives grins, which recognize collagen, fibronectin, and laminin, are present on osteoclasts, but avp3 is the principal integrin me- The author states that he has no conflicts of interest. diating bone resorption.('") This heterodimer, like all members 0 2008 American Society for Bone and Mineral Research OSTEOCLASTBIOLOGY AND BONERESORPTION I 17 FIG. 1. The osteoclast as a resorptive cell. Transmis- sion electron microscopy of a multinucleated primary rat osteoclast on bone. Note the extensive ruffled bor- der, close apposition of the cell to bone and the partially degraded matrix between the sealing zones. Courtesy of H. Zhao. of the (YV integrin family, recognizes the amino acid motif Arg- the osteoclast delivers effector molecules like HC1 and cathep- Gly-Asp (RGD), which is present in a variety of bone-residing sin K into the resorptive microenvironment. Osteoclasts are proteins such as osteopontin and bone sialoprotein. Thus, os- characterized by a unique cytoskeleton, which mediates the teoclasts attach to and spread on these substrates in an RGD- resorptive process. Specifically, when the cell contacts bone, it dependent manner and, most importantly, competitive ligands generates two polarized structures, which enable it to degrade arrest bone resorption in vivo. Proof of the pivotal role that skeletal tissue. In the first instance, a subset of acidified avp3 has in the resorptive process came with the generation of vesicles containing specific cargo, including cathepsin K and the p3 integrin knockout mouse, which develops a progressive other matrix metalloproteases (MMPs), are transported, prob- increase in bone mass because of osteoclast dysfunction.(33) ably through microtubules and actin, to the bone-apposed Based on a combination of these in vitro and in vivo observa- plasma membrane,(’*’ to which they fuse in a manner not cur- tions, small molecule inhibitors of osteoclast function that tar- rently understood, but which may involve PLEKHM1.(I3’ In- get avp3 have been developed.(”’ sertion of these vesicles into the plasmalemma results in for- Bone resorption also requires a polarization event in which mation of a villous structure, unique to the osteoclast, called the ruffled membrane. This resorptive organelle contains the abundant H’ transporting machinery to create the acidified microenvironment, whereas the accompanying exocytosis serves as the means by which cathepsin K is secreted (Fig. 3B). In addition to inducing ruffled membrane formation, contact with bone also prompts the osteoclast to polarize its fibrillar actin into a circular structure known as the “actin ring.” A separate “sealing zone” surrounds and isolates the acidified resorptive microenvironment in the active cell, but its compo- sition is almost completely unknown. The actin ring, like the ruffled membrane, is a hallmark of the degradative capacity of the osteoclast, because structural abnormalities of either occur in conditions of arrested resorption.(l4) In most cells, such as fibroblasts, matrix attachment prompts formation of stable structures known as focal adhesions that contain both integrins and a host of signaling and cytoskeletal
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