Development of New Osteoarthritis Mouse Model Through Acute Muscle Damage

Skeletal muscles play key roles in maintaining the homeostasis of the musculoskeletal system (MSK). The current models of osteoarthritis (OA) focus on the direct injury to the joint and have not tested whether direct muscle damage can lead to OA. This study’s objective was to investigate this possibility. We hypothesize that following muscle damage there will be periarticular muscle weakness causing joint damage. During muscle regeneration there will be a release of lipid signaling mediators into the circulation. The combination of biochemical and biomechanical modifications will alter the joint resulting in evidence of the onset of OA.This study was approved by the UTA IACUC. A total of 48 skeletally mature, young (28±1 weeks) C57BL/6 mice were used. The mice were blindly randomized into 4 groups: Baseline-Control, 4-Day post injection, 7-Day, and 1-month. Muscle damage was induced by intra-muscular (IM) injection of 50 μL of 1.2% Barium Chloride (BaCl2). The contralateral limb served as the sham control. Physical strength was accessed through grip strength. Locomotor activity was assessed using a force plate actimeter. Targeted lipidomics on serum was performed [1]. Paraffin embedded muscle was transversely cut at 7-μm thick and stained with H&E. The tibia was paraffin embedded, and 7-μm thick sections of the medial tibial plateau was stained with Safranin O/Fast Green. Before fixation of the tibia, bone and cartilage was accessed using Raman spectroscopy, and subchondral bone measured in μCT. Statistical analysis was conducted using ANOVA.The muscle damage in the TA showed a significant initial decrease in all limb grip strength (MD -54.62 p<.001 4-days post injury to baseline control). Strength significantly recovered over time (4-Day to 1-Month all limb grip MD 32.49 p<.001). Muscle regeneration was confirmed by our histological imaging of the TA which showed similar results to previous findings [2]. Serum lipidomics revealed a significant immune response with elevated concentration of Prostaglandin E2 (MD 2.752 p<.05), and lipid mediator derivatives of the EPA and DHA signaling pathway. The subchondral cortical shell showed significant increase in BV/TV by one month. Raman spectroscopy showed alterations in the cartilage consistent with our preliminary results in the histology. The articular cartilage showed a gradual fibrillation, and at 1-month post injury showed surface erosion and cartilage matrix loss consistent with the development of OA. While skeletal muscle has a remarkable ability to recover from injury, the resulting damage has prolonged effects on the joint. These finding suggest that a direct damage to the TA muscle could provide a new model in OA research, which are highly significant in the process of understanding the mechanism of OA. References: Wang, Z., et al (2017) Ana Chimica doi: 10.1016/j.aca.2017.07.024 ; Hardy, D., et al (2016) PLOS One doi: 10.1371/journal.pone.0147198 . LM, KA, JH, LB, and MB were supported by National Institutes of Health Grants: NIA 2-PO1AG039355, NIA R01AG056504; National Institute of Diabetes and Digestive and Kidney Diseases R01DK119066 to M.B.; and National Institutes of Neurological Disorders and Stroke (NINDS) 2-R01NS105621 to M.B. The authors are thankful for the generous support from the George W. and Hazel M. Jay Research Endowments, and the UTA College of Nursing and Health Center of Research and Scholarship. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.