Abstract
Bone continually adapts to meet changing physical and biological demands. Osteoblasts, osteoclasts, and osteocytes cooperate to integrate these physical and biochemical cues to maintain bone homeostasis. Although TGFβ acts on all three of these cell types to maintain bone homeostasis, the extent to which it participates in the adaptation of bone to mechanical load is unknown. Here, we investigated the role of the TGFβ pathway in load-induced bone formation and the regulation of Sclerostin, a mechanosensitive antagonist of bone anabolism. We found that mechanical load rapidly represses the net activity of the TGFβ pathway in osteocytes, resulting in reduced phosphorylation and activity of key downstream effectors, Smad2 and Smad3. Loss of TGFβ sensitivity compromises the anabolic response of bone to mechanical load, demonstrating that the mechanosensitive regulation of TGFβ signaling is essential for load-induced bone formation. Furthermore, sensitivity to TGFβ is required for the mechanosensitive regulation of Sclerostin, which is induced by TGFβ in a Smad3-dependent manner. Together, our results show that physical cues maintain bone homeostasis through the TGFβ pathway to regulate Sclerostin expression and the deposition of new bone.
Highlights
Osteocytes coordinate the adaptation of bone to changing physical demands on the skeleton [1]
We report that mechanical load represses TGFb activity, which is required for load-induced bone formation and the regulation of Sclerostin, an inhibitor of bone anabolism (Figure 5)
Intact TGFb signaling is required for load to repress Sclerostin expression and induce bone formation
Summary
Osteocytes coordinate the adaptation of bone to changing physical demands on the skeleton [1]. Upon sensing mechanical load through their canalicular processes, osteocytes initiate a series of biochemical signaling events that coordinate the activity of osteoblasts and osteoclasts to increase bone mass [2]. In this way, physical stimuli employ established biochemical pathways long known to participate in the maintenance of bone homeostasis, including parathyroid hormone (PTH) [3], insulin-like growth factor-I (IGF-1) [4], and prostaglandin signaling (PGE2) [5]. Sclerostin, a secreted protein expressed by osteocytes, responds to mechanical load and antagonizes bone formation [6]. Applied mechanical loads repress Sclerostin mRNA and protein expression [6], thereby releasing the brakes on new bone synthesis
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