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The R-spondin family of proteins are Wnt agonists, and the complete embryonic disruption of  Rspo2  results in skeletal developmental defects that recapitulate the phenotype observed with  Lrp5/6  deficiency. Previous work has shown that R-spondin-2 ( Rspo2 , RSPO2) is both highly expressed in Wnt-stimulated pre-osteoblasts and its overexpression induces osteoblast differentiation in the same cells, supporting its putative role as a positive autocrine regulator of osteoblastogenesis. However, the role of Rspo2 in regulating osteoblastogenesis and bone formation in postnatal bone has not been explored. Here we show that limb-bud progenitor cells from  Rspo2  knockout mice undergo reduced mineralization during osteoblastogenesis in vitro and have a corresponding alteration in their osteogenic gene expression profile. We also generated the first  Rspo2  conditional knockout (Rspo2 floxed ) mouse and disrupted  Rspo2  expression in osteoblast-lineage cells by crossing to the Osteocalcin-Cre mouse line (Ocn-Cre + Rspo2 f/f ). Ocn-Cre + Rspo2 f/f  male and female mice at 1, 3, and 6 months were examined. Ocn-Cre + Rspo2 f/f  mice are decreased in overall body size compared to their control littermates and have decreased bone mass. Histomorphometric analysis of 1-month-old mice revealed a similar number of osteoblasts and mineralizing surface per bone surface with a simultaneous decrease in mineral apposition and bone formation rates. Consistent with this observation, serum osteocalcin in 3-month-old Ocn-Cre + Rspo2 f/f  was reduced, and bone marrow-mesenchymal stem cells from Ocn-Cre + Rspo2 f/f  mice undergo less mineralization in vitro. Finally, gene expression analysis and immunohistochemistry of mature bone shows reduced beta-catenin signaling in Ocn-Cre + Rspo2 f/f . Overall, RSPO2 reduces osteoblastogenesis and mineralization, leading to reduced bone mass.

R-spondin-2 is a Wnt agonist that regulates osteoblast activity and bone mass