Losartan attenuates progression of osteoarthritis in the synovial temporomandibular and knee joints of a chondrodysplasia mouse model through inhibition of TGF-β1 signaling pathway. Issue 4 (April 2019)

• Record Type: Journal Article
• Authors: Thomas, M.; Fronk, Z.; Gross, A.; Willmore, D.; Arango, A.; Higham, C.; Nguyen, V.; Lim, H.; Kale, V.; McMillan, G.; Seegmiller, R.E.
• Is Part Of: Osteoarthritis and cartilage. Volume 27:Issue 4(2019)
• Page Start: 676
• Page End: 686
• Publication Date: 2019-04
• Subjects: Chondrodysplasia (cho, col11a1) -- High temperature requirement A1 serine protease (HtrA1) -- Losartan -- Osteoarthritis (OA) -- Temporomandibular joint (TMJ) -- Transforming growth factor-beta 1 (TGF-β1); Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Osteoarthritis -- Periodicals; Cartilage -- Periodicals; Arthrose -- Périodiques; Articulations -- Maladies -- Périodiques; 616.7223005
• DOI: 10.1016/j.joca.2018.12.016
• Languages: English
• ISSNs: 1063-4584

Abstract

Summary: Objective: Transforming growth factor beta 1 (TGF-β1) is implicated in osteoarthritis (OA). The purpose of this study was to explore the ability of Losartan to inhibit the inflammatory signaling pathway of TGF-β1 observed during osteoarthritic progression in the temporomandibular joint (TMJ) and knee joint using a genetic mouse model. Methods: A murine OA model displaying the heterozygous chondrodysplasia gene ( cho/+), a col11a1 mutation, was used to test this hypothesis. Following a 7-month treatment period with Losartan, the synovial joints were analyzed for histopathological improvement comparing two experimental groups. Tissues were fixed in paraformaldehyde, processed to paraffin section, and stained with Safranin O and Fast Green to visualize proteoglycans and collagen proteins in cartilage. Using the Modified Mankin scoring system, the degree of staining and OA progression were evaluated. Results: Results show heterozygous animals receiving Losartan having diminished degeneration of TMJ condylar and knee joint articular cartilage. This was confirmed in the TMJ and knee by a statistically significant decrease in the Mankin histopathology score. Decreased expression of HtrA1, a key regulator to the TGF-β1 signaling pathway, was demonstrated in vitro as well as in vivo, via Losartan inhibition. Conclusion: Using a genetic mouse model of OA, this study demonstrated the utility of Losartan to improve treatment of human OA in the TMJ and knee joint through inhibition of the TGF-β1 signaling cascade. We further demonstrated inhibition of HtrA1, the lowering of Mankin scores to wild type control levels, and the limiting of OA progressive damage with treatment of Losartan.