Implication of Cellular Senescence in Osteoarthritis: A Study on Equine Synovial Fluid Mesenchymal Stromal Cells

Abstract

Osteoarthritis (OA) is described as a chronic degenerative disease characterized by the loss of articular cartilage. Senescence is a natural cellular response to stressors. Beneficial in certain conditions, the accumulation of senescent cells has been implicated in the pathophysiology of many diseases associated with aging. Recently, it has been demonstrated that mesenchymal stem/stromal cells isolated from OA patients contain many senescent cells that inhibit cartilage regeneration. However, the link between cellular senescence in MSCs and OA progression is still debated. In this study, we aim to characterize and compare synovial fluid MSCs (sf-MSCs), isolated from OA joints, with healthy sf-MSCs, investigating the senescence hallmarks and how this state could affect cartilage repair. Sf-MSCs were isolated from tibiotarsal joints of healthy and diseased horses with an established diagnosis of OA with an age ranging from 8 to 14 years. Cells were cultured in vitro and characterized for cell proliferation assay, cell cycle analysis, ROS detection assay, ultrastructure analysis, and the expression of senescent markers. To evaluate the influence of senescence on chondrogenic differentiation, OA sf-MSCs were stimulated in vitro for up to 21 days with chondrogenic factors, and the expression of chondrogenic markers was compared with healthy sf-MSCs. Our findings demonstrated the presence of senescent sf-MSCs in OA joints with impaired chondrogenic differentiation abilities, which could have a potential influence on OA progression.

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

“…Treatments targeting senescent cells and the SASP have broad potential implications in the field of veterinary medicine as the hallmarks of aging ( 6 ) are highly conserved across species ( 227 , 228 ). These hallmarks include DNA damage ( 229 ), telomere shortening ( 230 , 231 ), aberrant proteostasis ( 232 ), epigenetic modifications ( 233 ), altered nutritional signaling ( 234 , 235 ), cell senescence ( 193 , 213 , 215 , 231 , 236 ), stem cell depletion ( 237 ), mitochondrial dysfunction ( 238 , 239 ), and abnormal inflammatory signaling ( 240 , 241 ). Treatment of age-related diseases in veterinary species may further serve to bolster preclinical evidence for use in humans.…”

“…The use of senotherapeutics for Alzheimer's disease is being evaluated ( 74 , 78 , 170 , 250 ) and canine or feline cognitive dysfunction may serve as a comparative naturally occurring model ( 249 , 251 – 253 ). Osteoarthritis is also significantly linked with age and cellular senescence ( 193 , 196 ). Due to similarities in cartilage thickness and joint volume, equine models are well suited comparisons of human osteoarthritis ( 175 , 176 , 254 ).…”

“…Similar to humans, sarcopenia (185, 245-247) (249,(251)(252)(253). Osteoarthritis is also significantly linked with age and cellular senescence (193,196). Due to similarities in cartilage thickness and joint volume, equine models are well suited comparisons of human osteoarthritis (175,176,254).…”

“…Transplantation of SC has precipitated an OA-like phenotype in mice when compared to transplantation of non-SC ( 192 ). A recent study evaluating synovial fluid in healthy horses and horses with OA found an increased number of senescent mesenchymal stem cells ( 193 ). The senescent cells displayed impaired chondrogenic differentiation ( 193 ) when compared with a non-senescent cell population, making them potential targets for senotherapeutics.…”

“…A recent study evaluating synovial fluid in healthy horses and horses with OA found an increased number of senescent mesenchymal stem cells ( 193 ). The senescent cells displayed impaired chondrogenic differentiation ( 193 ) when compared with a non-senescent cell population, making them potential targets for senotherapeutics. Murine models of rheumatoid arthritis (RA) found that dasatinib was protective against RA by inhibiting osteoclastogenesis through immunomodulatory effects ( 194 ).…”