蛋白酪氨酸磷酸酶SHP1调控间充质干细胞成骨与成脂分化平衡的作用及机制

An imbalance between normal adipogenesis and osteogenesis by mesenchymal stem cells (MSCs) has been shown to be related to various human metabolic diseases, such as obesity and osteoporosis; however, the underlying mechanisms remain elusive. We have confirmed the previous findings that mev/mev mice, whose SH2 domain-containing phosphatase 1 (SHP1) gene only maintains 25% activity, spontaneously developed osteoporosis. Moreover, we found that MSCs from mev/mev mice exhibited a significant reduction in osteoblast differentiation and a robust increase in adipocyte differentiation. Interestingly, we found that SHP1fl/flDermo1-Cre mice, losing SHP1 activity specifically in mesenchymal lineage cells including MSCs, showed higher body fat content and lower bone mass. Unexpectedly, we found that when treated MSCs with dexamathasone (Dex), a clinically well-known osteoporotic drug, the protein level of SHP1 was decreased significantly. Based on the well-estabolished Dex-induced osteoporosis mouse model and the platform of MSCs, from multiple angels and multiple layers, studies will be performed to investigate how SHP1 dictates the balance between adipogenesis and osteogenesis of MSCs and to explore the role of SHP1-mediated modulation on MSC differentiation in the pathogenesis of Dex-induced osteoporosis. Our studies will help us to expand our recognition about the regulatory roles of SHP1 in MSCs and osteoporosis pathogenesis, and provide the theoretic and experimental evidences to better treatment of related metabolic diseases including osteoporosis.

间充质干细胞（MSCs）成骨与成脂分化平衡的失调与人类多种代谢疾病如肥胖和骨质疏松密切相关，但具体机制尚不清楚。有报道称，蛋白酪氨酸磷酸酶（SHP1）基因突变的小鼠自发骨质疏松，对此我们进行了验证。同时发现，SHP1突变小鼠骨髓来源的MSCs难于成骨而更易于成脂。当在包括MSCs在内的中胚层来源的细胞上条件性敲除SHP1后，小鼠的脂肪增加而骨量减少。另外，我们发现用地塞米松（Dex）体外处理MSCs能显著下调SHP1的表达水平，而Dex的长期使用会导致骨质疏松。SHP1调控MSCs的作用是否与Dex诱导的骨质疏松有关，目前尚无报道。基于已有发现，我们将深入研究SHP1调控MSCs成骨与成脂分化平衡的作用与机制，并探讨SHP1调控MSCs在Dex诱导的骨质疏松致病中的作用，拓展对MSCs成骨与成脂分化平衡调控的认识，加深对骨质疏松致病机理的理解，为治疗包括骨质疏松在内的相关疾病提供理论指导。

间充质干细胞（MSCs）成骨与成脂分化平衡的失调与人类多种代谢疾病如肥胖和骨质疏松密切相关，但具体机制尚不清楚。有报道称，蛋白酪氨酸磷酸酶（SHP1）基因突变的小鼠自发骨质疏松，对此我们进行了验证。同时发现，SHP1突变小鼠骨髓来源的MSCs难于成骨而更易于成脂。当在包括MSCs在内的中胚层来源的细胞上条件性敲除SHP1后，小鼠的脂肪增加而骨量减少。我们的体外研究表明，SHP1缺陷的MSCs显示出明显减弱的成骨分化能力和显著增强的成脂分化能力。通过对分子机制的深入研究，我们发现，SHP1能够增强Wnt/β-catenin信号，而对BMP信号几乎没有影响。SHP1与GSK3β结合后，通过GSK3β pY216位点的去磷酸化作用，抑制了GSK3β的活性，β-catenin得到累积并入核，上调成骨分化相关转录因子的表达。反之，SHP1的缺失，则会增强GSK3β对β-catenin的磷酸化降解作用，降低MSCs成骨分化能力。综上所述，我们揭示了SHP1通过调控Wnt/β-catenin信号来维持MSCs的成骨成脂分化稳态，确保机体骨骼和脂肪组织的正常发育和功能的实现。我们的研究首次证明SHP1通过调控MSCs的分化方向从而调节骨和脂肪组织的发育。SHP1对MSCs分化的调控，是通过Wnt信号通路调节关键的转录因子来实现的。我们的研究进一步拓展了大家对骨骼发育和骨质疏松症发生的生理及病理方面的认识和理解，为干预骨质疏松症提供了理论依据。