Bone morphogenetic proteins (BMPs) are multifunctional proteins that regulate the fate of different cell types, including mesenchymal. BMPs promote the differentiation of mesenchymal cells into functional osteoblasts. Like other members of the transforming growth factor-β superfamily, BMPs elicit their cellular effects via specific types I and II serine/threonine receptors. The activated BMP type I receptor phosphorylates specific receptor-regulated (R)-Smad proteins, which assemble into heteromeric complexes with common partner (Co)-Smad4. Heteromeric Smad complexes efficiently translocate into the nucleus, where they regulate the transcription of target genes. Inhibitors of differentiation (Id) are genes that are specifically induced by BMPs in mesenchymal cells. Promoter analysis of Id1 indicates three distinct sequence elements that are sufficient and essential for efficient BMP-induced activation. Id1 was found to have an important effector function in various BMP-induced biological responses, including osteoblast differentiation.
The SOST gene product sclerostin is an osteocyte-derived negative regulator of bone formation and its deficiency causes the two closely related, rare skeletal dysplasia sclerosteosis and van Buchem disease. Sclerostin was found to inhibit BMP-stimulated bone formation in vitro and in vivo. Transcriptional profiling of osteoblastic cells treated with BMP in the absence or presence of sclerostin indicated that sclerostin specifically affects BMP and Wnt signaling among many other growth signaling pathways. Sclerostin, however, did not abrogate stimulation of direct BMP target genes, nor did we obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMP and Wnt-induced Wnt reporter construct activation. In conclusion, sclerostin abrogates BMP-stimulated bone formation by antagonizing Wnt signaling rather than directly inhibiting BMP signaling. High bone mass in sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling.
03 - 07 May 2008
European Society of Endocrinology