OPTN ameliorates chondrocyte apoptosis in temporomandibular joint osteoarthritis by modulating ER-mitochondria Ca transfer.

AIMS

Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease linked to disrupted chondrocyte activity and cartilage homeostasis. This study aimed to clarify the protective role of optineurin (OPTN) in preventing chondrocyte apoptosis during TMJ OA progression.

MATERIALS AND METHODS

Using bioinformatics analysis, Optn was identified as a key gene in chondrocyte regulation. We employed a unilateral anterior crossbite (UAC) model in vivo and Tunicamycin (TM) in vitro to investigate OPTN's role in TMJ OA. Makin scores and histological staining assessed cartilage degeneration, while flow cytometry measured chondrocyte apoptosis, mitochondrial, and endoplasmic reticulum (ER) calcium levels.

KEY FINDINGS

We demonstrated that OPTN deficiency accelerates arthritis progression by intensifying endoplasmic reticulum stress (ERS) and chondrocyte apoptosis both in vivo and in vitro. Mechanistically, in vitro data showed that OPTN interacted with glycogen synthase kinase 3 beta (GSK3β), modulating the inositol 1,4,5-triphosphate receptor (IP3R)/glucose-regulated protein 75 (GRP75)/voltage-dependent anion channel 1 (VDAC1) complex. This interaction affected ER-mitochondrial calcium transfer, elevating mitochondrial calcium, and promoting apoptosis. Inhibiting this calcium channel with SB216763 and 2-APB effectively reduced mitochondrial Ca overload and apoptosis.

SIGNIFICANCE

These findings reveal the crucial role of OPTN deficiency in TMJ OA pathogenesis and propose that targeting the IP3R-GRP75-VDAC1 complex to alleviate mitochondrial calcium could offer new therapeutic strategies for TMJ OA.