Abstract
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.
Highlights
Osteocytes act as mechanosensors in bone; the underlying mechanism remains poorly understood
In the present study, we demonstrate the importance of the focal adhesion protein, Kindlin-2, in the regulation of force adaptation during osteocyte mechanobiology
Through μCT scanning, we find that mice with Kindlin-2 loss in osteocytes exhibit remarkable osteopenia phenotype, which is only restricted to load-bearing bones, such as ulna, tibia, femur, and lumbar spine[48], but not in calvariae
Summary
Osteocytes act as mechanosensors in bone; the underlying mechanism remains poorly understood. Kindlin-2 loss in osteocytes impairs skeletal responses to mechanical stimulation in long bones. Kindlin-2-deficient osteocytes express abundant Sclerostin, contributing to bone loss in cKO mice. 1234567890():,; Bone constantly remodels in response to mechanical forces during physical exercise and daily life. This concept is the well-known “Wolff’s law” introduced by German anatomist and surgeon Julius Wolff in the 19th century[1]. This golden rule for bone remodeling is widely accepted to explain the forceinduced bone formation process and disuse-induced bone loss in humans[2,3,4] and animals[5]. These mechanosensors include osteocyte cytoskeleton, dendritic processes, integrin-based focal adhesions (FA), connexin-based gap junctions, primary cilium, ion channels, et al.[17]
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