Rspo1–LGR4 axis in BMSCs protects bone against radiation‐induced injury through the mTOR‐dependent autophagy pathway

Abstract While mesenchymal stem cells (MSCs) have been widely used to repair radiation‐induced bone damage, the molecular mechanism underlying the effects of MSCs in the maintenance of bone homeostasis under radiation stress remains largely unknown. In this study, the role and mechanisms of R‐spondin 1 (Rspo1)–leucine‐rich repeat‐containing G protein‐coupled receptor 4 (LGR4) axis on the initiation of self‐defense of bone mesenchymal stem cells (BMSCs) and maintenance of bone homeostasis under radiation stress were investigated. Interestingly, radiation increased levels of Rspo1 and LGR4 in BMSCs. siRNA knockdown of Rspo1 or LGR4 aggravated radiation‐induced impairment of self‐renewal ability and osteogenic differentiation potential of BMSCs. However, exogenous Rspo1 significantly attenuated radiation‐induced depletion of BMSCs, and promoted the lineage shift towards osteoblasts. This alteration was associated with the reversal of mammalian target of rapamycin (mTOR) activation and autophagy decrement. Pharmacological and genetic blockade of autophagy attenuated the radio‐protective effects of Rspo1, rendering BMSCs more vulnerable to radiation‐induced injury. Then bone radiation injury was induced in C57BL6J mice to further determine the radio‐protective effects of Rspo1. In mice, administration of Rspo1 recombinant protein alleviated radiation‐induced bone loss. Our results uncover that Rspo1–LGR4–mTOR–autophagy axis are key mechanisms by which BMSCs initiate self‐defense against radiation and maintain bone homeostasis. Targeting Rspo1–LGR4 may provide a novel strategy for the intervention of radiation‐induced bone damage.