| First Author | Zhao G | Year | 2020 |
| Journal | J Bone Miner Res | Volume | 35 |
| Issue | 11 | Pages | 2289-2300 |
| PubMed ID | 32634285 | Mgi Jnum | J:324140 |
| Mgi Id | MGI:7266783 | Doi | 10.1002/jbmr.4128 |
| Citation | Zhao G, et al. (2020) CCN1/Cyr61 Is Required in Osteoblasts for Responsiveness to the Anabolic Activity of PTH. J Bone Miner Res 35(11):2289-2300 |
| abstractText | CCN1/Cyr61 is a dynamically expressed matricellular protein that serves regulatory functions in multiple tissues. Previous studies from our laboratory demonstrated that CCN1 regulates bone maintenance. Using an osteoblast and osteocyte conditional knockout mouse model (Ccn1(OCN) ), we found a significant decrease in trabecular and cortical bone mass in vivo, in part through suppression of Wnt signaling since the expression of the Wnt antagonist sclerostin (SOST) is increased in osteoblasts lacking CCN1. It has been established that parathyroid hormone (PTH) signaling also suppresses SOST expression in bone. We therefore investigated the interaction between CCN1 and PTH-mediated responses in this study. We find that loss of Ccn1 in osteoblasts leads to impaired responsiveness to anabolic intermittent PTH treatment in Ccn1(OCN) mice in vivo and in osteoblasts from these mice in vitro. Analysis of Ccn1(OCN) mice demonstrated a significant decrease in parathyroid hormone receptor-1 (PTH1R) expression in osteoblasts in vivo and in vitro. We investigated the regulatory role of a non-canonical integrin-binding domain of CCN1 because several studies indicate that specific integrins are critical to mechanotransduction, a PTH-dependent response, in bone. These data suggest that CCN1 regulates the expression of PTH1R through interaction with the alphavbeta3 and/or alphavbeta5 integrin complexes. Osteoblasts that express a mutant form of CCN1 that cannot interact with alphavbeta3/beta5 integrin demonstrate a significant decrease in mRNA and protein expression of both PTH1R and alphav integrin. Overall, these data suggest that the alphavbeta3/beta5-binding domain of CCN1 is required to endow PTH signaling with anabolic activity in bone cells. (c) 2020 American Society for Bone and Mineral Research (ASBMR). |
