Journal Article

Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget’s Disease of Bone

Ralston, Stuart H., Tarrant, Teresa K., Lee, Hyun Ho, Rabjohns, Emily M., Berg, Kathryn, Mirando, Anthony, Hilton, Matthew J., Brozowski, Jaime M., Gladman, Justin, Eudy, Amanda M., Bowser, Jessica L., Hurst, Katlyn, Wani, Sachin, Ghosh, Arin, Rampersad, Rishi R., Ren, Yinshi

2023

Overview

Paget’s Disease of Bone (PDB) is a metabolic bone disease that is characterized by dysregulated osteoclast function leading to focal abnormalities of bone remodeling. It can lead to pain, fracture, and bone deformity. G protein-coupled receptor kinase 3 (GRK3) is an important negative regulator of G protein-coupled receptor (GPCR) signaling. GRK3 is known to regulate GPCR function in osteoblasts and preosteoblasts, but its regulatory function in osteoclasts is not well defined. Here, we report that Grk3 expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in Grk3 develop bone lesions similar to those seen in human PDB and other Paget’s Disease mouse models. We show that a deficiency in Grk3 expression enhances osteoclastogenesis in vitro and proliferation of hematopoietic osteoclast precursors in vivo but does not affect the osteoclast-mediated bone resorption function or cellular senescence pathway. Notably, we also observe decreased Grk3 expression in peripheral blood mononuclear cells of patients with PDB compared with age- and gender-matched healthy controls. Our data suggest that GRK3 has relevance to the regulation of osteoclast differentiation and that it may have relevance to the pathogenesis of PDB and other metabolic bone diseases associated with osteoclast activation.

• Publisher: MDPI AG,MDPI
• Subject: Analysis / Animal models / Animals / Autophagy / b-Adrenergic-receptor kinase / bone / Bone density / Bone diseases / Bone Diseases, Metabolic - pathology / Bone lesions / Bone marrow / Bone remodeling / Bone resorption / Bone Resorption - metabolism / Care and treatment / Cell lines / Cloning / Diagnosis / Flow cytometry / G protein-coupled receptor / G protein-coupled receptor kinase / G protein-coupled receptors / G proteins / G-Protein-Coupled Receptor Kinase 3 - genetics / Gene expression / Gene mutations / Genes / Genetic aspects / Genotype & phenotype / Health aspects / Hemopoiesis / Humans / Laboratory animals / Leukocytes (mononuclear) / Leukocytes, Mononuclear - metabolism / Metabolism / Mice / Mutation / Osteitis deformans / Osteitis Deformans - genetics / Osteitis Deformans - metabolism / osteoclast / Osteoclastogenesis / Osteoclasts / Osteoclasts - metabolism / Osteogenesis / Osteoprogenitor cells / Paget’s / Paget’s disease of bone / Pathogenesis / Peripheral blood mononuclear cells / Proteins / Senescence