Metastasis suppressor 1 controls osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling
Metastasis suppressor 1 controls osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling
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转移抑制因子 1 通过调节 Src-Wnt/β-catenin 信号传导控制成骨细胞分化和骨稳态
DOI：
10.1007/s00018-022-04147-y
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发表时间：
2022-02-01
影响因子：
8
通讯作者：
Wang, Baoli
中科院分区：
文献类型：
--
作者：
Chen, Meng;Shan, Liying;Wang, Baoli
转移抑制因子1 （Metastasis suppressor 1, MTSS1）在多种癌症的发生和转移中起抑制作用。迄今为止，MTSS1在骨髓基质祖细胞分化中的功能仍有待探索。在目前的研究中，我们研究了MTSS1是否以及如何在成骨细胞分化和骨稳态中发挥作用。我们的数据显示，在去卵巢小鼠和老龄小鼠的成骨细胞谱系中，MTSS1 mRNA在成骨细胞分化过程中表达上调，而在成骨细胞谱系中表达下调。功能研究表明，MTSS1促进骨髓基质祖细胞的成骨分化。机制探索发现，Src的失活和随后典型Wnt信号的激活参与了MTSS1诱导的成骨细胞分化。当Src同时过表达时，MTSS1过表达诱导的成骨分化增强被减弱，相反，在培养物中补充Src抑制剂后，MTSS1 siRNA对成骨分化的抑制被恢复。最后，体内转染MTSS1 siRNA至小鼠骨髓后，骨小梁骨量明显减少，骨小梁成骨细胞减少，骨髓脂肪细胞积累，骨小梁上磷酸src阳性细胞增多。破骨细胞数量未见明显变化。本研究揭示了MTSS1通过调节Src-Wnt/β-catenin信号传导促进成骨细胞分化和骨稳态。这也提示了MTSS1作为治疗骨质疏松症的新靶点的潜力。
Metastasis suppressor 1 (MTSS1) plays an inhibitory role in tumorigenesis and metastasis of a variety of cancers. To date, the function of MTSS1 in the differentiation of marrow stromal progenitor cells remains to be explored. In the current study, we investigated whether and how MTSS1 has a role in osteoblast differentiation and bone homeostasis. Our data showed that MTSS1 mRNA was upregulated during osteoblast differentiation and downregulated in the osteoblastic lineage cells of ovariectomized and aged mice. Functional studies revealed that MTSS1 promoted the osteogenic differentiation from marrow stromal progenitor cells. Mechanistic explorations uncovered that the inactivation of Src and afterward activation of canonical Wnt signaling were involved in osteoblast differentiation induced by MTSS1. The enhanced osteogenic differentiation induced by MTSS1 overexpression was attenuated when Src was simultaneously overexpressed, and conversely, the inhibition of osteogenic differentiation by MTSS1 siRNA was rescued when the Src inhibitor was supplemented to the culture. Finally, the in vivo transfection of MTSS1 siRNA to the marrow of mice significantly reduced the trabecular bone mass, along with the reduction of trabecular osteoblasts, the accumulation of marrow adipocytes, and the increase of phospho-Src-positive cells on the trabeculae. No change in the number of osteoclasts was observed. This study has unraveled that MTSS1 contributes to osteoblast differentiation and bone homeostasis through regulating Src-Wnt/β-catenin signaling. It also suggests the potential of MTSS1 as a new target for the treatment of osteoporosis.