Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation and inflammation of synovium, the specialized connective tissue that envelops the diarthrodial joint. Type 2 diabetes mellitus (DM) is often found in OA patients, with nearly double the incidence of arthritis reported in patients with diabetes (52%) than those without it (27%). The correlation between OA and DM has been attributed to similar risk factors, namely increasing age and joint loading due to obesity. However, a potential causative link is not well understood due to comorbidities involved with treating diabetic patients, such as high infection rates and poor healing response caused by hyperglycemia and insulin resistance. The purpose of this study was to investigate the effect of hyperglycemic and insulin culture conditions on synovium properties. It was hypothesized that modeling hyperglycemia-induced insulin resistance in synovium would provide novel insights of OA pathogenesis in DM patients. To simulate DM in the synovial joint, healthy synovium was preconditioned in either euglycemic (EG) or hyperglycemic (HG) glucose concentrations with insulin in order to induce the biological response of the diseased phenotype. Synovium biochemical composition was evaluated to determine ECM remodeling under hyperglycemic culture conditions. Concurrent changes in AKT phosphorylation, a signaling pathway implicated in insulin resistance, were measured along with gene expression data for insulin receptors, glucose transporters, and specific glycolysis markers involved in glucose regulation. Since fluid shear stress arising during joint articulation is a relevant upstream stimulus for fibroblast-like synoviocytes (FLS), the predominant cell type in synovium, FLS mechanotransduction was evaluated via intracellular calcium ([Ca2+]i). Incidence and length of primary cilia, a critical effector of cell mechanosensing, were measured as potential mechanisms to support differences in [Ca2+]i responses. Hyperglycemic culture conditions decreased collagen and GAG content compared to EG groups, while insulin recovered ECM constituents. FLS mechanosensitivity was significantly greater in EG and insulin conditions compared to HG and non-insulin treated groups. Hyperglycemic treatment led to decreased incidence and length of primary cilia and decreased AKT phosphorylation, providing possible links to the mechanosensing response and suggesting a potential correlation between glycemic culture conditions, diabetic insulin resistance, and OA development.
Highlights
Osteoarthritis (OA), the most common musculoskeletal disorder, is a degenerative condition that affects an estimated 250 million people worldwide (Rosa et al, 2009; Hamada et al, 2016; Stefani et al, 2019)
HG conditions exhibited decreased GAG content compared to EG groups in healthy synovium under both control and insulin treatment (p = .0296 and p = .0242, respectively) (Figure 3E)
Synovium function is compromised in patients with diabetes mellitus (DM) (Griffin and Huffman, 2016)
Summary
Osteoarthritis (OA), the most common musculoskeletal disorder, is a degenerative condition that affects an estimated 250 million people worldwide (Rosa et al, 2009; Hamada et al, 2016; Stefani et al, 2019). Joint loading due to obesity has been linked to articular cartilage damage in the development and progression of OA (Bramante et al, 2017; Silverstein et al, 2017; Sun et al, 2021). Increasing age is another known cause for the development of both diseases as adults above the age of 65 are more than twice as likely to develop either condition (Piva et al, 2015; Veronese et al, 2019). Patients diagnosed with OA have a 61% greater risk of developing DM compared to people without arthritis (Dong et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
