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• W3018264139 abstract "Purpose: OA is a whole joint disease, where breakdown of articular cartilage is considered a classical hallmark of disease pathophysiology and progression. Therefore, cartilage degeneration must be prevented or reversed in order to maintain and restore joint health. Previous studies reported the importance of Glycogen Synthase Kinase (GSK) -3 alpha and beta as key regulators in chondrocyte biology, but their roles in articular cartilage health and disease are not well understood. In this study, we examine the role of GSK-3 in knee joint OA as well as skeletal growth in cartilage-specific knock-out (KO) mice. Methods: Double KO was induced by oral administration of tamoxifen or vehicle, in skeletally mature cartilage-specific GSK3a/b-floxed mice bred to aggrecan-CreER mice. These mice were used for destabilization of medial meniscus (DMM) or Sham surgery to study post traumatic OA (PTOA). Operated knee joints were harvested 8 and 12 weeks after surgery from both male and female mice and processed for histological evaluation and molecular studies. Using the same method of gene KO in actively growing young mice, skeletal growth was measured using micro-computed tomography; while articular cartilage and growth plate in knee joints were examined by tissue histology and molecular expression by immunohistochemistry (IHC). Results: Histological evaluation of operated knee joints showed fibrillation and degradation of articular cartilage in DMM-operated control mice, whereas no such changes were observed in KO mice at 8 and 12 weeks after DMM surgery. However, both KO mice (Sham and DMM), showed similar proteoglycan loss in articular cartilage upon toluidine blue staining as well as loss of Sox9 expression by IHC, irrespective of the surgery type and sex. Surprisingly, these KO also showed complete closure of growth plates in their knee joint sections. These observations lead us to study skeletal growth in young KO. Young KO mice weighed less and had significantly shorter long bones compared to their control littermates within 25 days after induction of GSK-3 KO. At day 10 post induction of GSK-3 KO, we observed loss of growth plate integrity, proteoglycan content and Sox9 expression, by toluidine blue staining and IHC on knee joint sections, respectively; whereas TRAP positive staining was increased, indicating presence of more osteoclasts in the growth plate region and hence its accelerated resorption. These changes were significantly aggravated at day 25 time point, subsequently resulting in complete resorption and closure of growth plate in GSK-3 KO. Compared to growth plate, changes in articular cartilage were less severe suggesting that the two regions are differentially regulated by GSK-3. Furthermore, young KO did not survive past day 27 post induction of GSK-3 KO; while gene KO in skeletally mature mice did not affect the normal life span of these mice as we aged them up to 2 years. Conclusions: GSK-3 has a significant role in skeletal development, musculoskeletal health and disease. Retarded growth of skeletal elements in young GSK-3 KO is due to their compromised growth plates. GSK-3 KO mice showed reduced OA-like features, despite a reduced number of Sox9-expressing cells. We speculate that the loss of Sox9 expressing chondrocytes in articular cartilage might be responsible for reduced production of matrix degrading enzymes and hence, decreased breakdown of collagen matrix, thereby ameliorating OA-like symptoms in articular cartilage. These results suggest a differential spatial and temporal role of GSK-3 signaling in skeletal development and maintenance of musculoskeletal health in adults, as well as a potential therapeutic strategy to combat OA-like conditions." @default.
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• W3018264139 date "2020-04-01" @default.
• W3018264139 modified "2023-09-26" @default.
• W3018264139 title "GSK-3 knock out protects articular cartilage under osteoarthritic conditions but induces growth plate closure" @default.
• W3018264139 doi "https://doi.org/10.1016/j.joca.2020.02.146" @default.
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