The Potential Dual Roles of Metallothionein-1/-2 in Diabetic Osteoarthritis

Osteoarthritis (OA) is increasingly recognized as a chronic inflammatory degenerative joint disease. Recent evidence exhibits a higher prevalence of OA among patients with type II diabetes mellitus (T2DM). Metallothioneins (MTs) are important proteins involved in controlling physiology and pathophysiology. MT-1/MT-2 have been further found their positive correlation with OA progression, but their precise roles need more examination. This study aimed to investigate the role of MT-1/MT-2 in the development of diabetic OA and the underlying mechanisms. Cartilage was collected from patients with OA-only and T2DM-OA, and from rats classified as healthy, T2DM, and T2DM with destabilization of medial meniscus (DMM) surgery. Additionally, a cell model treated with high glucose (HG) or advanced glycation end products (AGEs) was used to investigate underlying mechanisms. Our results revealed that MT-1/MT-2 levels were elevated in cartilage from T2DM-OA patients and rats, as well as in T2DM rats subjected to DMM surgery. Similarly, primary chondrocytes treated with HG and AGE showed increased expression of MT-1/MT-2, with distinct distributions and regulatory mechanisms: (a) MT-1 enhanced MMP and transcription factor activity without affecting their expressions, whereas MT-2 increased both the activity and expression of MMPs and transcription factors; (b) MT-1 reduced IL6/IL8 expression, while MT-2 promoted it. Furthermore, this differential regulation appears to be mediated by BMP2 autocrine stimulation. These findings underscore the dual role of MT-1/MT-2 in simultaneously activating self-repair and degenerative processes, potentially influencing diabetic cartilage pathogenesis. Our study suggests that MT-1/MT-2 may serve as valuable theranostic targets for diabetic OA in future clinical applications.