Chemokine-Like Receptor 1 Is a Novel Wnt Target Gene that Regulates Mesenchymal Stem Cell Differentiation

Abstract

Abstract Bone remodeling is a dynamic process requiring the coordinated action of formative (osteoblast) and resorptive (osteoclast) cell populations. An imbalance of the development and function of these cell types underlies several chronic bone loss disorders such as osteoporosis. Increased bone marrow adipocyte numbers commonly occur with bone loss disorders and numerous studies have documented an inverse relationship between bone marrow fat and bone formation. Osteoblasts and adipocytes derive in a competitive fashion from a common mesenchymal stem cell (MSC) precursor. Generally, factors that promote MSC adipogenesis inhibit osteoblastogenesis and thereby, reduce bone formation. Previously we established that the secreted protein chemerin regulates adipogenic and osteoblastogenic differentiation of MSCs by signaling through chemokine-like receptor 1 (CMKLR1). However, the fundamental mechanisms by which chemerin/CMKLR1 influences lineage determination remain largely uncharacterized. Herein, we provide experimental evidence that chemerin/CMKLR1 regulates canonical Wnt signaling in MSCs by influencing the expression, subcellular location, and transcriptional activity of the central Wnt transducer, β-catenin. Moreover, we provide evidence that CMKLR1 is a novel Wnt responsive gene that functions in a negative feedback loop to limit osteoblastogenic Wnt signaling. Mechanistically, this entails Notch-dependent changes in the expression and function of key adipogenic and osteoblastogenic transcription factors, cell cycle proteins and chromatin remodeling enzymes. Consistent with this, MSCs from CMKLR1 knockout (−/−) mice exhibited similar dependency on Notch signaling to maintain osteoblastogenic differentiation. Taken together, our findings support a fundamental biological function for chemerin/CMKLR1 to balance osteoblastogenic and adipogenic signaling and thereby contribute to the maintenance of pluripotency in MSCs.