| First Author | Ono M | Year | 2011 |
| Journal | J Bone Miner Res | Volume | 26 |
| Issue | 1 | Pages | 193-208 |
| PubMed ID | 20684029 | Mgi Jnum | J:179857 |
| Mgi Id | MGI:5304253 | Doi | 10.1002/jbmr.205 |
| Citation | Ono M, et al. (2011) WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity. J Bone Miner Res 26(1):193-208 |
| abstractText | Wnt-induced secreted protein 1 (WISP-1/CCN4) is a member of the CCN family that is highly expressed in skeletal tissue and in osteoprogenitor cells induced to differentiate in vitro. To determine the function of WISP-1 during osteogeneis, osteogenic bone marrow stromal cells (BMSCs) were transduced with WISP-1 adenovirus (adWISP-1) in the presence or absence of bone morphogenetic protein 2 (BMP-2) adenovirus (adBMP-2). WISP-1 overexpression enhanced the ability of BMP-2 to direct BMSCs toward osteogenic differentiation and appeared to work by stimulating Smad-1/5/8 phosphorylation and activation. The ability of WISP-1 to enhance BMP-2 activity also was shown in vivo using an ectopic osteogenesis assay with BMSCs transduced with WISP-1, BMP-2, or both. When BMSCs were infected with lentivirus containing human WISP1 shRNA, they formed less bone in vivo and were less responsive to BMP-2, confirming that WISP-1 and BMP-2 have a functional interaction. Immunoprecipitation (IP) and Western blot analysis showed that WISP-1 bound directly to BMP-2 and showed that WISP-1 increased BMP-2 binding to hBMSCs in a dose-dependent fashion. To understand how WISP-1 enhanced BMP-2 signaling, the influence of WISP-1 on integrin expression was analyzed. WISP-1 induced the mRNA and protein levels of alpha(5)-integrin and, further, was found to bind to it. Antibody-blocking experiments showed that the BMP-2 binding to BMSCs that was enhanced by WISP-1 was completely neutralized by treatment with anti-integrin alpha(5)beta(1) antibody. Pilot studies and the use of transgenic mice that overexpressed human WISP-1 in preosteoblasts had increased bone mineral density (BMD), trabecular thickness, and bone volume (BV/TV) over wild-type controls, supporting observations using human osteoprogenitors that WISP-1 has a positive influence on osteogenesis in vivo. In conclusion, these studies show, for the first time, that WISP-1 has a positive influence on bone cell differentiation and function and may work by enhancing the effects of BMP-2 to increase osteogenesis through a mechanism potentially involving binding to integrin alpha(5)beta(1). |
