Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis
Abstract Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understan...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-07-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-017-1375-0 |
| _version_ | 1830459102165204992 |
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| author | Susan MacLauchlan Maria A. Zuriaga José J. Fuster Carla M. Cuda Jennifer Jonason Fernanda Behzadi Jennifer Parker Duffen G. Kenneth Haines Tamar Aprahamian Harris Perlman Kenneth Walsh |
| author_facet | Susan MacLauchlan Maria A. Zuriaga José J. Fuster Carla M. Cuda Jennifer Jonason Fernanda Behzadi Jennifer Parker Duffen G. Kenneth Haines Tamar Aprahamian Harris Perlman Kenneth Walsh |
| author_sort | Susan MacLauchlan |
| collection | DOAJ |
| description | Abstract Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. Methods We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Results Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. Conclusions These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease. |
| first_indexed | 2024-12-21T10:50:27Z |
| format | Article |
| id | doaj.art-f6922a141c014a60b70f6e82f20750a8 |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-21T10:50:27Z |
| publishDate | 2017-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-f6922a141c014a60b70f6e82f20750a82022-12-21T19:06:40ZengBMCArthritis Research & Therapy1478-63622017-07-0119111110.1186/s13075-017-1375-0Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritisSusan MacLauchlan0Maria A. Zuriaga1José J. Fuster2Carla M. Cuda3Jennifer Jonason4Fernanda Behzadi5Jennifer Parker Duffen6G. Kenneth Haines7Tamar Aprahamian8Harris Perlman9Kenneth Walsh10Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of MedicineMolecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of MedicineMolecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of MedicineDivision of Rheumatology, Department of Medicine, Northwestern University, Feinberg School of MedicineUniversity of Rochester Medical Center, School of Medicine and DentistryMolecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of MedicineMolecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of MedicineDepartment of Pathology, Icahn School of Medicine at Mount SinaiRenal Section, Boston University School of MedicineDivision of Rheumatology, Department of Medicine, Northwestern University, Feinberg School of MedicineMolecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of MedicineAbstract Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. Methods We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Results Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. Conclusions These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.http://link.springer.com/article/10.1186/s13075-017-1375-0Rheumatoid arthritisWnt5aInflammationOsteoclast fusion |
| spellingShingle | Susan MacLauchlan Maria A. Zuriaga José J. Fuster Carla M. Cuda Jennifer Jonason Fernanda Behzadi Jennifer Parker Duffen G. Kenneth Haines Tamar Aprahamian Harris Perlman Kenneth Walsh Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis Arthritis Research & Therapy Rheumatoid arthritis Wnt5a Inflammation Osteoclast fusion |
| title | Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis |
| title_full | Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis |
| title_fullStr | Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis |
| title_full_unstemmed | Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis |
| title_short | Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis |
| title_sort | genetic deficiency of wnt5a diminishes disease severity in a murine model of rheumatoid arthritis |
| topic | Rheumatoid arthritis Wnt5a Inflammation Osteoclast fusion |
| url | http://link.springer.com/article/10.1186/s13075-017-1375-0 |
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