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

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 and Taku Saito ()
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Song Ho Chang: The University of Tokyo
Daisuke Mori: The University of Tokyo
Hiroshi Kobayashi: The University of Tokyo
Yoshifumi Mori: The University of Tokyo
Hideki Nakamoto: The University of Tokyo
Keita Okada: The University of Tokyo
Yuki Taniguchi: The University of Tokyo
Shurei Sugita: The University of Tokyo
Fumiko Yano: The University of Tokyo
Ung-il Chung: The University of Tokyo
Joo-ri Kim-Kaneyama: Showa University School of Medicine
Motoko Yanagita: Kyoto University
Aris Economides: Regeneron Pharmaceuticals, Inc.
Ernesto Canalis: UConn Heath
Di Chen: Rush University Medical Center
Sakae Tanaka: The University of Tokyo
Taku Saito: The University of Tokyo

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09491-5

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