Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway.

Nature communications 2019 Mar 29

filter terms:

Exposure of articular cartilage to excessive mechanical loading is deeply involved in the pathogenesis of osteoarthritis. Here, we identify gremlin-1 as a mechanical loading-inducible factor in chondrocytes, detected at high levels in middle and deep layers of cartilage after cyclic strain or hydrostatic pressure loading. Gremlin-1 activates nuclear factor-κB signalling, leading to subsequent induction of catabolic enzymes. In mice intra-articular administration of gremlin-1 antibody or chondrocyte-specific deletion of Gremlin-1 decelerates osteoarthritis development, while intra-articular administration of recombinant gremlin-1 exacerbates this process. Furthermore, ras-related C3 botulinum toxin substrate 1 activation induced by mechanical loading enhances reactive oxygen species (ROS) production. Amongst ROS-activating transcription factors, RelA/p65 induces Gremlin-1 transcription, which antagonizes induction of anabolic genes such as Sox9, Col2a1, and Acan by bone morphogenetic proteins. Thus, gremlin-1 plays essential roles in cartilage degeneration by excessive mechanical loading.

Citation

Song Ho Chang, Daisuke Mori, Hiroshi Kobayashi, Yoshifumi Mori, Hideki Nakamoto, Keita Okada, Yuki Taniguchi, Shurei Sugita, Fumiko Yano, Ung-Il Chung, Joo-Ri Kim-Kaneyama, Motoko Yanagita, Aris Economides, Ernesto Canalis, Di Chen, Sakae Tanaka, Taku Saito. Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway. Nature communications. 2019 Mar 29;10(1):1442