Zhou Yi, Mohan Aron, Moore Douglas C, Lin Liangjun, Zhou Frank Li, Cao Jay, Wu Qian, Qin Yi-Xian, Reginato Anthony M, Ehrlich Michael G, Yang Wentian
*Stem Cell Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA; Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York, USA; Engineering and Applied Science, California Institute of Technology, Pasadena, California, USA; U.S. Department of Agriculture Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, USA; Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA; and Division of Rheumatology, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA.
*Stem Cell Program, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA; Department of Orthopaedics, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA; Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York, USA; Engineering and Applied Science, California Institute of Technology, Pasadena, California, USA; U.S. Department of Agriculture Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, USA; Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA; and Division of Rheumatology, Brown University Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island, USA
FASEB J. 2015 May;29(5):1635-45. doi: 10.1096/fj.14-260844. Epub 2015 Jan 15.
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.
在生理和疾病状态下，调控破骨细胞（OC）发育和功能的基因仍未被完全了解。Shp2（含Src同源2结构域的蛋白酪氨酸磷酸酶2）是一种广泛表达的细胞质蛋白酪氨酸磷酸酶，参与调节巨噬细胞集落刺激因子（M-CSF）和核因子κB受体活化因子配体（RANKL）引发的信号传导；然而，其在破骨细胞生成和骨稳态中的作用尚不清楚。我们采用组织特异性基因敲除方法，使小鼠破骨细胞中的Shp2表达失活。Shp2突变小鼠表现为骨石化，其骨体积（BV）/总体积（TV）显著增加（+42.8%），骨小梁数量（Tb.N）增加（+84.1%），结构模型指数增加（+119%），而骨小梁厚度（Tb.Th）降低（-34.1%），骨小梁间距（Tb.Sp）降低（-41.0%）。生化分析表明，Shp2通过上调活化T细胞核因子细胞质1（Nfatc1）的表达来促进RANKL诱导的巨大多核破骨细胞形成，Nfatc1是破骨细胞终末分化所必需的主要转录因子。然而，Shp2缺失对M-CSF依赖的破骨细胞前体存活和增殖影响极小。相反，其缺陷会阻止破骨细胞前体融合和多核破骨细胞形成，并减少骨基质吸收。此外，Shp2的药理学干预足以在体外阻止前破骨细胞融合。这些发现揭示了一种新机制，即Shp2通过促进前破骨细胞融合来调控破骨细胞生成。Shp2或其信号传导伙伴可能作为药理学靶点，用于局部和/或系统性地调控破骨细胞数量，从而治疗与破骨细胞相关的疾病，如假体周围骨溶解和骨质疏松症。
