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Objectives and questions: Osteoarthritis (OA) is a progressive inflammatory disease characterized by cartilage degradation and joint-wide structural damage. To investigate its pathogenesis, the murine destabilization of the medial meniscus (DMM) model serves as highly relevant proxy for human OA due to its cross-species biomechanical similarities. The neuropeptideα-melanocyte-stimulating hormone (α-MSH) exhibits potent anti-inflammatory and chondroprotective properties, primarily through the melanocortin 1 receptor (MC1R). This study evaluated whether intra-articular supplementation with the stable analog NDP-α-MSH or the derivative KdPT can modulate anti-inflammatory and senescence-associated pathways to delay OA progression.

Material and methods: OA was induced in 12-week-old male wild type (C57Bl/6J) mice via destabilization of the medial meniscus (DMM) surgery, with sham-operated mice serving as controls. Animals received intra-articular injections of NDP-α-MSH, KdPT, or PBS at 1, 4, 8, and 12 weeks post-surgery. After 8 and 16 weeks post DMM/Sham surgery, evaluation included nighttime locomotion monitoring, histological assessment of cartilage degradation, and immunohistochemical analysis of MC1R- and TUNEL-positive chondrocytes. Additionally, cartilage stiffness was quantified via atomic force microscopy (AFM), and systemic inflammatory markers were measured using Luminex multiplex ELISA.

Results: DMM surgery induced significant cartilage degradation, which was markedly inhibited by NDP-α-MSH and KdPT treatment 16 weeks post-surgery compared to PBS controls. While MC1R-positive chondrocytes decreased in NDP-α-MSH treated DMM mice relative to sham controls, plasma levels of pro-inflammatory markers (CRP, IL-1β, IL-6, IL-18) were significantly reduced in the NDP-α-MSH group at 8 and 16 weeks post-surgery. Furthermore, KdPT administration resulted in greater total distance moved and longer moving times, yet it significantly reduced average locomotor velocity, indicating a pattern of persistent but slower-paced exploration compared to other treatment groups.

Discussion and conclusions: These findings demonstrate that intra-articular applied α-MSH analogs effectively mitigate cartilage loss and systemic inflammation following joint destabilization. The reduction in circulating cytokines and the preservation of joint integrity suggest that targeting melanocortin signaling offers a viable therapeutic strategy for disease-modifying OA treatment.