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
Emily M. Rabjohns,
Rishi R. Rampersad,
Arin Ghosh,
Katlyn Hurst,
Amanda M. Eudy,
Jaime M. Brozowski,
Hyun Ho Lee,
Yinshi Ren,
Anthony Mirando,
Justin Gladman,
Jessica L. Bowser,
Kathryn Berg,
Sachin Wani,
Stuart H. Ralston,
Matthew J. Hilton,
Teresa K. Tarrant
Affiliations
Emily M. Rabjohns
Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA
Rishi R. Rampersad
Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA
Arin Ghosh
College of Arts and Sciences, Duke University, Durham, NC 27510, USA
Katlyn Hurst
College of Arts and Sciences, Duke University, Durham, NC 27510, USA
Amanda M. Eudy
Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA
Jaime M. Brozowski
Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA
Hyun Ho Lee
Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA
Yinshi Ren
Department of Orthopaedic Surgery, University of Texas Southwestern, Dallas, TX 75390, USA
Anthony Mirando
Department of Orthopedics, Duke University, Durham, NC 27710, USA
Justin Gladman
Pratt School of Engineering, Duke University, Durham, NC 27710, USA
Jessica L. Bowser
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Kathryn Berg
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Sachin Wani
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Stuart H. Ralston
Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Matthew J. Hilton
Department of Orthopedics, Duke University, Durham, NC 27710, USA
Teresa K. Tarrant
Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USA
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.
