Tissue inhibitor of metalloproteinase 1 (TIMP1) has various biological activities including the regulation of cell growth and differentiation. However, its role in bone homeostasis and remodeling remains poorly understood. In this study, we investigated the effects of TIMP1 on osteoblast and osteoclast activity at both cellular and molecular level using siRNA-mediated knockdown techniques. Our results show that knockdown of TIMP1 stimulates proliferation and survival, but decreases apoptosis in osteoblastic MC3T3-E1 cells, suggesting that TIMP1 inhibits cell growth. TIMP1 also dampens differentiation of committed osteoblasts, as well as osteoblastogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). We further show that the modulation of TIMP1 on osteoblast activity is independent of its MMP inhibition. Importantly, we uncover that TIMP1 suppresses osteoblast growth and differentiation by targeting the AKT pathway, and this is associated with TIMP1-mediated induction of PTEN via its binding to the cell surface receptor CD44. Therefore, our results highlight a novel TIMP1/CD44/PTEN/AKT signaling nexus that functions as a suppressor of osteoblast activity. Moreover, we show that TIMP1 also inhibits osteoclast differentiation in osteoclast precursor RAW 264.7 cells by targeting the AKT. In conclusion, our results demonstrate that TIMP1 can act as a suppressor of growth and differentiation of osteoblasts and differentiation of osteoclasts through the negative regulation of the AKT pathway. We propose that TIMP1 may serve as a potential target for low bone mass-related skeletal diseases, such as osteoporosis.

中文翻译：

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金属蛋白酶1的组织抑制剂通过靶向AKT途径抑制成骨细胞的生长和分化以及破骨细胞的分化。

金属蛋白酶1（TIMP1）的组织抑制剂具有多种生物学活性，包括调节细胞生长和分化。然而，其在骨稳态和重塑中的作用仍知之甚少。在这项研究中，我们使用siRNA介导的敲除技术研究了TIMP1在细胞和分子水平上对成骨细胞和破骨细胞活性的影响。我们的结果表明，敲低TIMP1刺激增殖和存活，但减少成骨细胞MC3T3-E1细胞的凋亡，表明TIMP1抑制细胞生长。TIMP1还抑制定型成骨细胞的分化，以及骨髓来源的间充质干细胞（BMSC）的成骨细胞生成。我们进一步表明，TIMP1对成骨细胞活性的调节独立于其MMP抑制作用。重要的，我们发现，TIMP1通过靶向AKT途径抑制成骨细胞的生长和分化，这与TIMP1介导的PTEN通过与细胞表面受体CD44的结合有关。因此，我们的结果强调了一种新型的TIMP1 / CD44 / PTEN / AKT信号传导联系，起着抑制成骨细胞活性的作用。此外，我们显示TIMP1还通过靶向AKT抑制破骨细胞前体RAW 264.7细胞中的破骨细胞分化。总之，我们的结果表明TIMP1可以通过AKT途径的负调控来抑制成骨细胞的生长和分化以及破骨细胞的分化。我们建议TIMP1可能作为低骨量相关的骨骼疾病，如骨质疏松症的潜在目标。