| First Author | Nguyen J | Year | 2020 |
| Journal | Bone | Volume | 131 |
| Pages | 115148 | PubMed ID | 31715338 |
| Mgi Jnum | J:285648 | Mgi Id | MGI:6387367 |
| Doi | 10.1016/j.bone.2019.115148 | Citation | Nguyen J, et al. (2020) CYLD, a mechanosensitive deubiquitinase, regulates TGFbeta signaling in load-induced bone formation. Bone 131:115148 |
| abstractText | Many signaling pathways involved in bone homeostasis also participate in the anabolic response of bone to mechanical loading. For example, TGFbeta signaling coordinates the maintenance of bone mass and bone quality through its effects on osteoblasts, osteoclasts, and osteocytes. TGFbeta signaling is also essential for the mechanosensitive formation of new bone. However, the mechanosensitive mechanisms controlling TGFbeta signaling in osteocytes remain to be determined, particularly those that integrate TGFbeta signaling with other early responses to mechanical stimulation. Here, we used an in vivo mouse hindlimb loading model to identify mechanosensitive molecules in the TGFbeta pathway, and MLO-Y4 cells to evaluate their interactions with the prostaglandin E2 (PGE2) pathway, which is well-known for its rapid response to mechanical stimulation and its role in bone anabolism. Although mRNA levels for several TGFbeta ligands, receptors, and effectors were unchanged, the level of phosphorylated Smad2/3 (pSmad2/3) was reduced in tibial bone as early as 3h after early mechanical stimulation. We found that PGE2 and its receptor, EP2, repress pSmad2/3 levels and transactivation of Serpine1 in osteocytes. PGE2 and EP2 control the level of pSmad2/3 through a proteasome-dependent mechanism that relies on the deubiquitinase CYLD. CYLD protein levels were also reduced in the tibiae within 3h of mechanical loading. Using CYLD-deficient mice, we found that CYLD is required for the rapid load-mediated repression of pSmad2/3 and for load-induced bone formation. These data introduce CYLD as a mechanosensitive deubiquitinase that participates in the prostaglandin-dependent repression of TGFbeta signaling in osteocytes. |
