DDIT3 aggravates TMJOA cartilage degradation via Nrf2/HO-1/NLRP3-mediated autophagy

Objective: DNA damage-inducible transcript 3 (DDIT3), as a downstream transcription factor of endoplasmic reticulum stress, is reported to regulate chondrogenic differentiation under physiological and pathological state. However, the specific involvement of DDIT3 in the degradation of condylar cartilage of temporomandibular joint osteoarthritis (TMJOA) is unclarified.

Design: The expression patterns of DDIT3 in condylar cartilage from monosodium iodoacetate-induced TMJOA mice were examined to uncover the potential role of DDIT3 in TMJOA. The Ddit3 knockout (Ddit3^-/-) mice and their wildtype littermates (Ddit3^+/+) were used to clarify the effect of DDIT3 on cartilage degradation. Primary condylar chondrocytes and ATDC5 cells were applied to explore the mechanisms of DDIT3 on Autophagy and extracellular matrix (ECM) degradation in chondrocytes. The Autophagy Inhibitor chloroquine (CQ) was used to determine the effect of DDIT3-inhibited Autophagy in vivo.

Results: DDIT3 were highly expressed in condylar cartilage from TMJOA mice. Ddit3 knockout alleviated condylar cartilage degradation and subchondral bone loss, compared with their wildtype littermates. In vitro study demonstrated that DDIT3 exacerbated ECM degradation in chondrocytes induced by TNF-α through inhibiting Autophagy. The intraperitoneal injection of CQ further confirmed that Ddit3 knockout alleviated cartilage degradation in TMJOA through activating Autophagy in vivo.

Conclusions: Our findings identified the crucial role of DDIT3-inhibited Autophagy in condylar cartilage degradation during the development of TMJOA.

Autophagy; Cartilage degradation; DDIT3; NLRP3; Nrf2; Osteoarthritic chondrocytes.