Therapeutic blockade of platelet-derived growth factor receptor-like protein attenuates cartilage degeneration and modulates cytokines in a spontaneous osteoarthritis mouse model.

Objective: Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by the progressive breakdown of articular cartilage, affecting 10-15 % of older adults worldwide. There remains an urgent need for effective therapies to prevent chondrocyte loss, extracellular matrix (ECM) degradation, and OA progression.

Methods: Through LC-MS/MS-based secretome analysis, we identified platelet-derived growth factor receptor-like protein (PDGFRL) as a novel factor significantly upregulated in osteoarthritic cartilage. To investigate its functional role, we utilized human cartilage plugs, STR/ort mice with spontaneous OA, and primary chondrocyte cultures to model ex vivo, in vivo, and in vitro conditions, respectively, allowing for comprehensive evaluation of PDGFRL's effects on chondrocytes and its underlying mechanisms.

Results: PDGFRL expression was markedly elevated in both human and murine osteoarthritic cartilage. In the ex vivo human cartilage plug model, PDGFRL exerted deleterious effects by inducing chondrocyte clustering and reducing SOX9 expression. In vitro, PDGFRL treatment increased phosphorylation of Chk-2, p53, and eNOS, along with IGFBP3 secretion, indicating activation of apoptotic and ECM-degradative pathways. In STR/ort mice, anti-PDGFRL antibody treatment alleviated OA progression by reducing matrix-nonproducing chondrocytes, decreasing OARSI scores, suppressing aggrecan degradation and MMP-13 expression, and restoring SOX9 levels. Additionally, anti-PDGFRL treatment modulated systemic cytokine profiles by increasing chondroprotective IL-13 and IP-10, while elevating cartilage-destructive leptin and IL-7R. In contrast, exogenous PDGFRL protein administration did not exacerbate OA severity.

Conclusion: Our findings identify PDGFRL as a therapeutic target, and suggest that inhibition using specific antibodies may offer a novel strategy to preserve cartilage integrity and slow disease progression.