The role of R-spondins and their receptors in bone metabolism.

R-spondins are a family of four secreted proteins and act as agonists of the canonical Wnt/β-catenin signaling pathway. They are broadly expressed in different phases of skeleton tissues. Recently, three closely related leucine-rich repeat containing G-protein-coupled receptors (Lgr4/5/6) have been identified as the new and exact receptors of R-spondins. On the cell surface, R-spondins binding with Lgr4/5/6 and Znrf3/Rnf43 lead to reduced turnover of Wnts-receptors and potentiate Wnt/β-catenin signaling pathway which is critical for the control of bone development and remodeling. There has been a growing interest in understanding the role and mechanism of R-spondins and their receptors in multiple biological processes, including bone development and metabolism. Recent advances in the R-spondins revealed the potential modulatory effect on osteoblastogenesis and bone formation and provided a new avenue for the investigation of adult bone metabolism. The receptors of Lgr4/5/6 and stabilized β-catenin are essential to the regulatory effect of Rspos on skeleton. The findings on Rspo/Lgr signaling might have clinical potentials for the treatment of bone loss related diseases.