A role for G protein-coupled receptor 137b in bone remodeling in mouse and zebrafish

• Published in: Bone (New York, N.Y.) Vol. 127; pp. 104 - 113
• Main Authors: Urso, K., Caetano-Lopes, J., Lee, P.Y., Yan, J., Henke, K., Sury, M., Liu, H., Zgoda, M., Jacome-Galarza, C., Nigrovic, P.A., Duryea, J., Harris, M.P., Charles, J.F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Animals; Base Sequence; Bone; Bone and Bones - pathology; Bone Remodeling - physiology; Bone Resorption - pathology; Cell Differentiation; GPR137b; Homeostasis; Loss of Function Mutation - genetics; Mice, Inbred C57BL; Osteoclast; Osteoclasts - metabolism; Osteogenesis; Receptors, G-Protein-Coupled - metabolism; Zebrafish; Zebrafish - physiology; Zebrafish Proteins - metabolism; Zebrafish; Osteoclast; Bone; GPR137b
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2019.06.002

G protein-coupled receptor 137b (GPR137b) is an orphan seven-pass transmembrane receptor of unknown function. In mouse, Gpr137b is highly expressed in osteoclasts in vivo and is upregulated during in vitro differentiation. To elucidate the role that GPR137b plays in osteoclasts, we tested the effect of GPR137b deficiency on osteoclast maturation and resorbing activity. We used CRISPR/Cas9 gene editing in mouse-derived ER-Hoxb8 immortalized myeloid progenitors to generate GPR137b-deficient osteoclast precursors. Decreasing Gpr137b in these precursors led to increased osteoclast differentiation and bone resorption activity. To explore the role of GPR137b during skeletal development, we generated zebrafish deficient for the ortholog gpr137ba. Gpr137ba-deficient zebrafish are viable and fertile and do not display overt morphological defects as adults. However, analysis of osteoclast function in gpr137ba−/− mutants demonstrated increased bone resorption. Micro-computed tomography evaluation of vertebral bone mass and morphology demonstrated that gpr137ba-deficiency altered the angle of the neural arch, a skeletal site with high osteoclast activity. Vital staining of gpr137ba−/− fish with calcein and alizarin red indicated that bone formation in the mutants is also increased, suggesting high bone turnover. These results identify GPR137b as a conserved negative regulator of osteoclast activity essential for normal resorption and patterning of the skeleton. Further, these data suggest that coordination of osteoclast and osteoblast activity is a conserved process among vertebrates and may have similar regulation. •GPR137b is a seven-pass transmembrane receptor expressed by osteoclasts•Decreasing Gpr137b in osteoclast precursors increased osteoclast differentiation and bone resorption activity in vitro•Loss-of-function gpr137ba zebrafish mutants demonstrated increased bone resorption•We propose that GPR137b is a conserved negative regulator of osteoclastogenesis in vertebrates