cZFP609 Tethering BiP Alleviates Cartilage Degradation in Osteoarthritis via Remedying Aberrant ER‐Mitochondrial Contacts

Vascular dysfunction is implicated in the pathogenesis of osteoarthritis (OA). Herein, we utilized smooth muscle specific human Sirt1 transgenic (sm Sirt1 ‐Tg) mice characterized by vascular homeostasis to prepare an OA model to validate vasculature‐derived articular cartilage protective factors. The OA of sm Sirt1 ‐Tg mice exhibited significantly reduced cartilage destruction and pain sensitivity, accompanied by increased proteoglycans content and collagen type II (Col2ɑ) expression and decreased matrix metallopeptidase 13 (MMP13) and p53 expression. Vascular smooth muscle cell‐derived cZFP609 was highly enriched in the articular cartilage and plasma of sm Sirt1 ‐Tg mice. Overexpression of cZFP609 abrogated TNFα‐induced endoplasmic reticulum (ER) stress and fine‐tuned the mitochondrial homeostasis in chondrocytes. Mechanistically, cZFP609, located in the cytoplasm, interacted with binding immunoglobulin protein (BiP) to stabilize the BiP oligomeric form. This interaction reduced the level of active BiP monomer that induced not only ER stress via activating IRE1α (inositol‐requiring enzyme 1α) signaling but also mediated the formation of ER–mitochondria contacts (ERMCs). Increased oligomeric BiP by overexpression of cZFP609 suppressed ERMC‐driven aberrant ER–mitochondria communication and diminished lipid peroxidation and ferroptosis, which contributed to maintaining mitochondrial homeostasis and alleviating cartilage degeneration in OA. Taken together, these results elucidate a beneficial cZFP609‐driven feed‐forward circuit that can be effectively targeted to stem the progression of OA.