Steven L Teitelbaum

..The past five years have witnessed important insights into osteoclast formation and function. Many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis...

..M-CSF and its receptor, c-Fms, therefore present as candidate therapeutic targets in states of inflammatory bone erosion...

..Using a lentiviral-based strategy to express beta3 mutants in beta3(-/-) mice, we also show that beta3(S752), but not beta3(Y747/Y759), is important for osteoclastic bone resorption in vivo...

..Furthermore, this same add-back approach identifies important roles for Tyr-697 and Tyr-721 in collaborating with Tyr-559 to recruit a multimeric signaling complex that can transduce signals from c-Fms to the actin cytoskeleton...

..Thus, IL-1 mediates the osteoclastogenic effect of TNF by enhancing stromal cell expression of RANKL and directly stimulating differentiation of osteoclast precursors...

..These studies provide support for increased RANKL expression associated with MAGP1 deficiency and provide a link to altered TGF-β signaling as a possible causative signaling pathway regulating RANKL expression in MAGP1Δ osteoblasts...

..These counterbalancing events yield indistinguishable bones of WT and SLAP-/- mice which contain equal numbers of osteoclasts in basal and stimulated conditions...

..Thus, ritonavir may represent a bone-sparing PI capable of preventing development of osteopenia in patients currently on HAART...

..Finally, c-Fms-activated Syk also exerts its OC cytoskeleton-organizing effect in a SLP-76/Vav3-dependent manner...

..The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine...

..Using specific small molecule inhibitors we find that a combination of the Src family kinase, phosphatidylinositol 3-kinase/Akt, phospholipase C, and ERK pathways mediates macrophage proliferation in response to M-CSF...

..Consequently, pathologically or pharmacologically inhibited resorption eventuates in arrested osteoblast activity...

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..Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway...

..FHL2 is, therefore, an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated RANK signaling...

..Consequently, Syk(Y317F) abolishes M-CSF- and integrin-stimulated Syk ubiquitination. Thus, Cbl/Syk(Y317) association negatively regulates OC function and therefore is essential for maintenance of skeletal homeostasis...

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..Our data provide genetic and biochemical evidence that uncovers an epistatic signaling pathway linking the receptor tyrosine kinase c-Fms to the immune adaptor DAP12 and the cytoskeleton...

..These data suggest that Cdc42 regulates osteoclast formation and function and may represent a promising therapeutic target for prevention of pathological bone loss...

..Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to αvβ3, organizes the cell's cytoskeleton...

..These results implicate Limd1 as a potentially important regulator of osteoclast development under conditions of stress...

..Furthermore, the same cells plated onto osteopontin, adhere poorly and fail to phosphorylate c-Src or Pyk2, two kinases central to organization of the osteoclast cytoskeleton...

..Thus, talin1 and Rap1 are critical for resorptive function, and their selective inhibition in mature osteoclasts retards pathological bone loss...

..Absence of any component of this signaling pathway compromises osteoclast cytoskeletal organization and abridges bone resorption...

..Moreover, we provide genetic and biochemical evidence for the role of Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. Thus, Vav3 is a potential new target for antiosteoporosis therapy...

..Therefore, the bone-forming capacity of osteoblasts is distinct from their ability to maintain hematopoietic stem cells in chronic inflammatory conditions...

..Together, our findings suggest that MAGP1 is a regulator of bone remodeling, and its absence results in osteopenia associated with an increase in osteoclast number...

..Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and alpha v beta3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target...

..We proposed that radiolabeled RGD peptides could be used to detect osteoclasts in lytic bone lesions...

..This review focuses on these and other molecules that mediate osteoclast differentiation or function and thus serve as candidate anti-osteoporosis therapeutic targets...

..Thus, Fyn is a pro-resorptive SFK, which exerts its effects by prompting proliferation and differentiation while attenuating apoptosis of OC lineage cells...

..The most pragmatic aspect of our findings is that successful therapeutic inhibition of c-Src, in the context of the osteoclast, will require its stringent targeting...

..Therefore, synaptotagmin VII plays an important role in bone remodeling and homeostasis by modulating secretory pathways functionally important in osteoclasts and osteoblasts...

..These observations raise caution that therapeutic inhibition of NOTCH signaling may adversely accelerate bone loss in humans...

..Thus, we have identified specific tyrosine residues in the cytoplasmic tail of c-Fms that are critical for transmitting M-CSF-initiated signals individually required for OC formation or function, respectively...

..Thus, in response to RANKL, paxillin associates with myosin IIA to contract the osteoclast cytoskeleton, thereby promoting its bone-degrading capacity...

..Consistent with osteoclasts modulating the osteoblast-suppressive effect of dexamethasone, GC receptor-deficient mice are protected from the steroid's inhibition of bone formation...

..Thus, while c-Fms and alpha(v)beta(3) collaborate in the osteoclastogenic process via shared activation of the ERK/c-Fos signaling pathway, the integrin is essential for matrix degradation...

..These data demonstrate a novel, biologically relevant means of regulating NF-kappaB signaling, with upstream control and kinetics distinct from the classical IkappaBalpha pathway...

..Consistent with osteoclasts modulating the osteoblast-suppressive effect of DEX, GRoc-/- mice are protected from the steroid's inhibition of bone formation...

..Estrogen deprivation, therefore, promotes RANKL expression and bone resorption in association with upregulation of the IL-17 effector, Act1, supporting the concept that post-menopausal osteoporosis is a disorder of innate immunity...

..The failure of osteoblasts to normalize Dap12(-/-) osteoclasts indicates that functionally relevant quantities of OSCAR ligand do not reside in bone-forming cells...

..Thus, unoccupied alpha(v)beta3 integrin regulates osteoclast apoptosis via a component of the integrin that is different than that regulating resorption...

..Thus, halofuginone, which is presently FDA-approved for treatment of scleroderma, is a candidate therapeutic for post-menopausal osteoporosis...

..Thus, the beta3 cytoplasmic domain is responsible for activation of specific intracellular signals leading to cytoskeletal reorganization critical for OC function...

..Signals from alphavbeta3 and/or c-Fms activate Syk and Vav3, originally defined by their function in lymphoid cells. Genetic depletion of either protein generates a strong bone phenotype, underscoring the promise of osteoimmunobiology...

..Thus, SytVII-deficient mice experience suppressed bone resorption and formation with the latter deficiency predominant thereby yielding osteoporosis characterized by attenuated remodeling...

..Thus, Rac1 and Rac2 are mutually compensatory. Unlike Cdc42 deficiency, their combined absence does not impact upon differentiation but promotes severe osteopetrosis by dysregulating the osteoclast cytoskeleton...

..Achieving an understanding of the mechanisms by which the three cytokines affect the osteoclast has resulted in a number of active and candidate therapeutic targets...

..Integrin/bone recognition also promotes formation of actin rings, which surround the ruffled border, thereby isolating the focus of skeletal degradation from the general extracellular space...

..Thus, NF-kappaB appears to be the centerpiece of inflammatory-osteolytic arthritis and direct inhibition of this transcription factor by unique and novel I-kappaB mutant proteins blocks manifestation of the disease...

..These findings are in keeping with a putative link between autophagy genes and human skeletal homeostasis...

..Hurchla, M. A., Deng, H., Floyd, D., Berdy, A., Prior, J. L., Piwnica-Worms, D., Teitelbaum, S. L., Ross, F. P., Weilbaecher, K. N. Dissection of platelet and myeloid cell defects by conditional targeting of the beta3-integrin subunit...

..In this issue of Cell Stem Cell, Wu et al. (2010) demonstrate that this event is mediated by osteoclastic mobilization of active transforming growth factor β1, which is inhibited by a common antiosteoporosis drug...

..Our studies have investigated whether absence of the alphavbeta3 integrin modifies the ability of c-Fms to induce Rho GTPases, and the implications for formation of the osteoclast cytoskeleton...

..In these diseases, osteoclast activity causes bone loss that leads to pain, deformity, and fracture. Thus, osteoclasts are critical for normal bone function, but their activity must be controlled...

..Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis...

..These results suggest cytokine plasticity may help to fine-tune specific tumor necrosis factor (TNF)-family cytokine/receptor pair selectivity...

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..In this issue of Cell, Lee et al. (2007) demonstrate in mice that bone regulates the insulin/glucose axis and energy metabolism, providing a new framework for approaching common disorders of bioenergetics...

..Collectively, our data suggest that Rab3D modulates a post-TGN trafficking step that is required for osteoclastic bone resorption...

..These preliminary data suggest alphavbeta5 integrin's presence on osteoclast precursors may inhibit of osteoclast formation...