M Thomas1, Z Fronk2, A Gross3, D Willmore2, A Arango1, C Higham1, V Nguyen1, H Lim1, V Kale4, G McMillan1, R E Seegmiller5. 1. Roseman University of Health Sciences, College of Dental Medicine, South Jordan, UT 84095, USA. 2. Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA. 3. Roseman University of Health Sciences, College of Dental Medicine, South Jordan, UT 84095, USA. Electronic address: agross1@roseman.edu. 4. Roseman University of Health Sciences, College of Pharmacy, South Jordan, UT 84095, USA. 5. Roseman University of Health Sciences, College of Dental Medicine, South Jordan, UT 84095, USA; Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.
Abstract
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.
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.
Authors: Mina Wang; Lu Liu; Claire Shuiqing Zhang; Zehuan Liao; Xianghong Jing; Marc Fishers; Luopeng Zhao; Xiaobai Xu; Bin Li Journal: J Pain Res Date: 2020-06-15 Impact factor: 3.133
Authors: Mustafa M Tashkandi; Saqer F Alsaqer; Thabet Alhousami; Faiza Ali; Yu-Chiao Wu; Jennifer Shin; Pushkar Mehra; Larry M Wolford; Louis C Gerstenfeld; Mary B Goldring; Manish V Bais Journal: Sci Rep Date: 2020-11-19 Impact factor: 4.379