SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion

Abstract

Genes that regulate osteoclast (OC) development and function in both physiologic and disease conditions remain incompletely understood. Shp2 (the Src homology-2 domain containing protein tyrosine phosphatase 2), a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, is implicated in regulating M-CSF and receptor activator of nuclear factor-κB ligand (RANKL)-evoked signaling; its role in osteoclastogenesis and bone homeostasis, however, remains unknown. Using a tissue-specific gene knockout approach, we inactivated Shp2 expression in murine OCs. Shp2 mutant mice are phenotypically osteopetrotic, featuring a marked increase of bone volume (BV)/total volume (TV) (+42.8%), trabeculae number (Tb.N) (+84.1%), structure model index (+119%), and a decrease of trabecular thickness (Tb.Th) (-34.1%) and trabecular spacing (Tb.Sp) (-41.0%). Biochemical analyses demonstrate that Shp2 is required for RANKL-induced formation of giant multinucleated OCs by up-regulating the expression of nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1), a master transcription factor that is indispensable for terminal OC differentiation. Shp2 deletion, however, has minimal effect on M-CSF-dependent survival and proliferation of OC precursors. Instead, its deficiency aborts the fusion of OC precursors and formation of multinucleated OCs and decreases bone matrix resorption. Moreover, pharmacological intervention of Shp2 is sufficient to prevent preosteoclast fusion in vitro. These findings uncover a novel mechanism through which Shp2 regulates osteoclastogenesis by promoting preosteoclast fusion. Shp2 or its signaling partners could potentially serve as pharmacological targets to regulate the population of OCs locally and/or systematically, and thus treat OC-related diseases, such as periprosthetic osteolysis and osteoporosis.

Inhibition of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Facilitates CD31^hiEndomucin^hi Blood Vessel and Bone Formation in Ovariectomized Mice

“…Global deletion of SHP-2 leads to early embryonic lethality [19,20], and induced SHP-2-deficient mice exhibit an osteopetrotic phenotype and generate much fewer osteoclasts [21]. The role of SHP-2 in osteoclastogenesis has been confirmed by a recent report showing that SHP-2 is required for multinucleated osteoclast formation by promoting preosteoclast fusion via the RANKL/NFATc1 signaling axis [11]. Wang et al generated monocyte/macrophagespecific SHP2 deficient mice and found that the mice exhibit mild osteopetrosis and their derived bone marrow macrophages have decreased osteoclast formation potential [22].…”

“…However, previous studies have demonstrated that SHP-1 is a negative modulator of osteoclastogenesis, and mice lacking SHP-1 have increased number of osteoclasts [11,23,24]. Moreover, a recent study by Tang et al showed that SHP-1 inhibition repressed osteoblast differentiation and mineralization [25].…”

“…3C and D). Since PDGF-BB is the key effector that mediates the pro-angiogenic activities of preosteoclasts 9 and NSC-87877 is able to inhibit the fusion of preosteoclasts into osteoclasts [11], the promotion of preosteoclast PDGF-BB-induced angiogenesis may be a mechanism by which NSC-87877 prevents osteoporosis.…”

“…A recent study by Zhou et al revealed that inactivation of SHP-2 by using the osteoclasts-specific SHP-2 knockout mice or the SHP-2 inhibitor (NSC-87877) could markedly block the fusion of mononuclear preosteoclasts into multinucleated osteoclasts and impair the bone resorption activity of osteoclasts [11], suggesting that SHP-2 could potentially serve as a pharmacological target to inhibit osteoclastogenesis and increase the numbers of preosteoclasts. In consideration of the results of our previous study showing that preosteoclasts were capable of secreting PDGF-BB to stimulate CD31 hi Emcn hi vessel formation and enhance osteogenesis, we hypothesized that inhibition of SHP-2 might be a promising approach for promoting the generation of this crucial blood vessel subtype, further enhancing bone formation and preventing estrogen deficiency-induced osteoporosis.…”

Glutamic acid ameliorates estrogen deficiency–induced menopausal-like symptoms in ovariectomized mice

“…Based on our findings that GA enhanced new bone formation, we investigated the osteogenic activity of GA using MG-63 cells. Osteoporosis is associated with osteoclast proliferation [61], and thus, bone loss was prevented by stimulating the process of osteoblast proliferation and suppressing the process of osteoclastogenesis in the OVX mice [62]. Osteoblast proliferation is regulated via binding to the ERE of the E 2 -ER complex and ERK activation [63,64].…”