Osteoclasts: What Do They Do and How Do They Do It?

Teitelbaum, Steven L.

doi:10.2353/ajpath.2007.060834

Cited by 622 publications

(509 citation statements)

References 95 publications

(105 reference statements)

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“…However, the role of IFN-␥ in pathological bone disease is largely controversial. Previously, it has been reported that IFN-␥ can inhibit the critical osteoclast regulator, receptor activator of NFB ligand (RANKL), by activating ubiquitin-mediated degradation of its signaling pathway adaptor protein TRAF-6 (7,8). Mice deficient for IFN-␥ or its receptor develop enhanced bone loss associated with collagen-induced arthritis (9 -11).…”

Section: Ifn-␥mentioning

confidence: 99%

Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases

Hurchla

Deng

et al. 2009

Journal of Biological Chemistry

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Interferon-␥ (IFN-␥ IFN-␥3 is a multifunctional cytokine produced mainly by NK cells and activated T cells that plays a critical role in host immune responses against pathogens and cancer (1). Mice deficient in IFN-␥, the R1 subunit of the IFN-␥ receptor, or the transcription factor STAT1 are more susceptible to spontaneous tumor development (1-3). IFN-␥ has also been found to have direct anti-proliferative and pro-apoptotic effects on tumor cells in animal models (4, 5); however, administration of high dose IFN-␥ to patients with advanced renal and ovarian cancer has had only limited success and failed to improve overall survival (1, 6).IFN-␥ has been shown to regulate bone cell differentiation and function with complex effects on skeletal health. However, the role of IFN-␥ in pathological bone disease is largely controversial. Previously, it has been reported that IFN-␥ can inhibit the critical osteoclast regulator, receptor activator of NFB ligand (RANKL), by activating ubiquitin-mediated degradation of its signaling pathway adaptor protein 8). Mice deficient for IFN-␥ or its receptor develop enhanced bone loss associated with collagen-induced arthritis (9 -11). In contrast, Gao et al. (12) recently found that IFN-␥ indirectly stimulates osteoclast formation and bone loss after ovariectomy via antigen-driven T cell activation, resulting in the production of osteoclast-activating factors. Interestingly, IFN-␥ has been used to treat infantile osteopetrosis in which patients suffered from high bone mass secondary to osteoclast dysfunction or osteoblast hyperactivity, but the mechanism of action may be through modulation of the host immune system rather than direct effects on bone cells (13-15). However, the role of IFN-␥ in the treatment of osteolytic bone metastases has not been elucidated.We evaluated the effects of IFN-␥ in HTLV-1-Tax transgenic mice that develop osteolytic bone tumors and hypercalcemia (16,17). Previously, it was shown that HTLV-1-Taxmice develop increased numbers of soft tissue tumors with enhanced tumor-associated angiogenesis and up-regulation of vascular endothelial growth factor expression; however, the impact on bone metastases and hypercalcemia in these mice * This work was supported, in whole or in part, by National Institutes of Health Grants PPG CA100730 and R01 CA 097250 (to Z. X., M. H., H. D., M. C. E., D. H. F., E. A. H., and K. N. W.), Grant T32 CA09547 (cancer biology training grant to O. U. and M. H.), and Grant RO1 CA100730 (to T. J. R. and W. P. D. and NCRR to S. S.), as well as by the St. Louis Men's Club Against Cancer (to K. N. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Section: Ifn-␥mentioning

confidence: 99%

Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases

Hurchla

Deng

et al. 2009

Journal of Biological Chemistry

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“…First, macrophages are closely related to bone-resorbing osteoclasts and share a dependence on the lineage-specific growth factor CSF-1 (2). Although inflammatory macrophages are well acknowledged for their roles in immunity and chronic inflammation, it is less widely recognized that there are populations of resident tissue macrophages present in most tissues throughout development and adulthood (e.g., alveolar macrophages and Kupffer cells (3)).…”

mentioning

confidence: 99%

Osteal Tissue Macrophages Are Intercalated throughout Human and Mouse Bone Lining Tissues and Regulate Osteoblast Function In Vitro and In Vivo

Chang

Raggatt

Alexander

et al. 2008

The Journal of Immunology

618

646

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Resident macrophages are an integral component of many tissues and are important in homeostasis and repair. This study examines the contribution of resident tissue macrophages to bone physiology. Using immunohistochemistry, we showed that a discrete population of resident macrophages, OsteoMacs, was intercalated throughout murine and human osteal tissues. OsteoMacs were distributed among other bone lining cells within both endosteum and periosteum. Furthermore, OsteoMacs were coisolated with osteoblasts in murine bone explant and calvarial preparations. OsteoMacs made up 15.9% of calvarial preparations and persisted throughout standard osteoblast differentiation cultures. Contrary to previous studies, we showed that it was OsteoMacs and not osteoblasts within these preparations that responded to pathophysiological concentrations of LPS by secreting TNF. Removal of OsteoMacs from calvarial cultures significantly decreased osteocalcin mRNA induction and osteoblast mineralization in vitro. In a Transwell coculture system of enriched osteoblasts and macrophages, we demonstrated that macrophages were required for efficient osteoblast mineralization in response to the physiological remodeling stimulus, elevated extracellular calcium. Notably, OsteoMacs were closely associated with areas of bone modeling in situ, forming a distinctive canopy structure covering >75% of mature osteoblasts on diaphyseal endosteal surfaces in young growing mice. Depletion of OsteoMacs in vivo using the macrophage-Fas-induced apoptosis (MAFIA) mouse caused complete loss of osteoblast bone-forming surface at this modeling site. Overall, we have demonstrated that OsteoMacs are an integral component of bone tissues and play a novel role in bone homeostasis through regulating osteoblast function. These observations implicate OsteoMacs, in addition to osteoclasts and osteoblasts, as principal participants in bone dynamics.

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“…Osteoclasts are highly specialized cells that have the capacity to resorb bone or, perhaps more accurately, to invade mineralized tissue in a regulated manner (8). They express very high levels of a subpopulation of V-ATPases (a3-and d2-containing V-ATPases) that are targeted to the ruffled plasma membrane, a subdomain of the plasma membrane, when osteoclasts encounter bone (9 -11).…”

mentioning

confidence: 99%