RRC ID 57733
Author Chang SH, Mori D, Kobayashi H, Mori Y, Nakamoto H, Okada K, Taniguchi Y, Sugita S, Yano F, Chung UI, Kim-Kaneyama JR, Yanagita M, Economides A, Canalis E, Chen D, Tanaka S, Saito T.
Title Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway.
Journal Nat Commun
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.
Volume 10(1)
Pages 1442
Published 2019-3-29
DOI 10.1038/s41467-019-09491-5
PII 10.1038/s41467-019-09491-5
PMID 30926814
PMC PMC6441020
MeSH Anabolic Agents / pharmacology Animals Bone Morphogenetic Proteins / pharmacology Chondrocytes Humans Intercellular Signaling Peptides and Proteins / metabolism* Male Mice, Inbred C57BL Mice, Knockout NF-kappa B / metabolism* Osteoarthritis / metabolism* Osteoarthritis / pathology* Reactive Oxygen Species / metabolism Signal Transduction* Stress, Mechanical Weight-Bearing rac1 GTP-Binding Protein / metabolism
IF 11.878
Times Cited 18
Human and Animal Cells ATDC5(RCB0565)