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
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...
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MDPI AG
2023-03-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/7/981 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Emily M. Rabjohns |
| collection | DOAJ |
| description | 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 <i>Grk3</i> expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in <i>Grk3</i> develop bone lesions similar to those seen in human PDB and other Paget’s Disease mouse models. We show that a deficiency in <i>Grk3</i> 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 <i>Grk3</i> 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. |
| first_indexed | 2024-03-11T05:41:20Z |
| format | Article |
| id | doaj.art-d4ebb64765294ed991aa8881105b3d2b |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T05:41:20Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d4ebb64765294ed991aa8881105b3d2b2023-11-17T16:27:36ZengMDPI AGCells2073-44092023-03-0112798110.3390/cells12070981Aged G Protein-Coupled Receptor Kinase 3 (Grk3)-Deficient Mice Exhibit Enhanced Osteoclastogenesis and Develop Bone Lesions Analogous to Human Paget’s Disease of BoneEmily M. Rabjohns0Rishi R. Rampersad1Arin Ghosh2Katlyn Hurst3Amanda M. Eudy4Jaime M. Brozowski5Hyun Ho Lee6Yinshi Ren7Anthony Mirando8Justin Gladman9Jessica L. Bowser10Kathryn Berg11Sachin Wani12Stuart H. Ralston13Matthew J. Hilton14Teresa K. Tarrant15Division of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USADivision of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USACollege of Arts and Sciences, Duke University, Durham, NC 27510, USACollege of Arts and Sciences, Duke University, Durham, NC 27510, USADivision of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USADivision of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USADivision of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USADepartment of Orthopaedic Surgery, University of Texas Southwestern, Dallas, TX 75390, USADepartment of Orthopedics, Duke University, Durham, NC 27710, USAPratt School of Engineering, Duke University, Durham, NC 27710, USADepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USACentre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UKCentre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UKCentre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UKDepartment of Orthopedics, Duke University, Durham, NC 27710, USADivision of Rheumatology and Immunology, Duke University Department of Medicine, Durham, NC 27710, USAPaget’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 <i>Grk3</i> expression increases during osteoclast differentiation in both human and mouse primary cells and established cell lines. We also show that aged mice deficient in <i>Grk3</i> develop bone lesions similar to those seen in human PDB and other Paget’s Disease mouse models. We show that a deficiency in <i>Grk3</i> 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 <i>Grk3</i> 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.https://www.mdpi.com/2073-4409/12/7/981boneosteoclastPaget’sPaget’s disease of boneG protein-coupled receptor kinaseG protein-coupled receptor |
| spellingShingle | 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 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 Cells bone osteoclast Paget’s Paget’s disease of bone G protein-coupled receptor kinase G protein-coupled receptor |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | bone osteoclast Paget’s Paget’s disease of bone G protein-coupled receptor kinase G protein-coupled receptor |
| url | https://www.mdpi.com/2073-4409/12/7/981 |
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