Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, China.
Commun Biol. 2021 Mar 25;4(1):402. doi: 10.1038/s42003-021-01950-4.
Osteocytes act as mechanosensors in bone; however, the underlying mechanism remains poorly understood. Here we report that deleting Kindlin-2 in osteocytes causes severe osteopenia and mechanical property defects in weight-bearing long bones, but not in non-weight-bearing calvariae. Kindlin-2 loss in osteocytes impairs skeletal responses to mechanical stimulation in long bones. Control and cKO mice display similar bone loss induced by unloading. However, unlike control mice, cKO mice fail to restore lost bone after reloading. Osteocyte Kindlin-2 deletion impairs focal adhesion (FA) formation, cytoskeleton organization and cell orientation in vitro and in bone. Fluid shear stress dose-dependently increases Kindlin-2 expression and decreases that of Sclerostin by downregulating Smad2/3 in osteocytes; this latter response is abolished by Kindlin-2 ablation. Kindlin-2-deficient osteocytes express abundant Sclerostin, contributing to bone loss in cKO mice. Collectively, we demonstrate an indispensable novel role of Kindlin-2 in maintaining skeletal responses to mechanical stimulation by inhibiting Sclerostin expression during osteocyte mechanotransduction.
成骨细胞作为骨骼中的机械感受器；然而，其潜在机制仍知之甚少。在这里，我们报告在成骨细胞中缺失 Kindlin-2 会导致承重长骨严重的骨质疏松症和机械性能缺陷，但非承重的颅骨则不会。成骨细胞中 Kindlin-2 的缺失会损害骨骼对长骨机械刺激的反应。对照组和 cKO 小鼠在去负荷诱导的骨丢失方面表现出相似的特征。然而，与对照组小鼠不同的是，cKO 小鼠在重新加载后无法恢复丢失的骨。成骨细胞 Kindlin-2 的缺失会损害体外和体内的黏附斑（FA）形成、细胞骨架组织和细胞定向。流体切应力呈剂量依赖性地增加成骨细胞中 Kindlin-2 的表达，并通过下调 Smad2/3 降低 Sclerostin 的表达；而这一反应在 Kindlin-2 缺失时被废除。成骨细胞中缺乏 Kindlin-2 会表达大量的 Sclerostin，导致 cKO 小鼠的骨丢失。总之，我们证明了 Kindlin-2 在机械转导过程中通过抑制 Sclerostin 的表达，对维持骨骼对机械刺激的反应具有不可或缺的新作用。
