The Role of BMPs in Bone Anabolism and their Potential Targets SOST and DKK1

Nobuhiro      Kamiya

Abstract

Bone morphogenetic proteins (BMPs) were discovered in 1965 as potent inducers of ectopic bone formation when implanted subcutaneously. BMP2, BMP4, BMP6, and BMP7 are osteoinductive, and BMP2 and BMP7 are currently approved for clinical applications such as bone fracture healing and spine surgery. Although BMPs’ role in bone formation is well known, the current clinical data supporting their effectiveness are not robust, possibly in part because BMPs affect bone resorption as well. BMPs can reduce bone mass by inducing osteoclastogenesis via the RANKL-OPG pathway, which is a critical regulator of osteoclasts by osteoblasts. BMPs have both bone anabolic and catabolic effects by affecting multiple cell types in bone such as mesenchymal cells, chondrocytes, osteoblasts, osteoclasts, and endothelial cells. We recently generated an osteoblast-targeted deletion of BMP signaling using a Cre-loxP strategy and found that BMP signaling in osteoblasts can inhibit Wnt signaling through the Wnt inhibitors DKK1 and SOST. Loss-of-function of either DKK1 or SOST, which are downstream targets of BMPs, causes a high bone mass phenotype in humans and mice, suggesting an importance of DKK1 and SOST for bone mass regulation. There are many bone anabolic effectors that control bone mass such as BMPs, PTH, and Wnt inhibitors. This article will focus on BMPs’ effects on bone anabolism and propose a potential network of the bone mass mediators BMPs, PTH, and SOST. We believe it is important to understand this network to guide the clinical application of bone anabolic agents.

Keywords: BMP, bone anabolic agent, bone mass, DKK1, osteoblast, osteoclast, SOST/Sclerostin, Wnt