Excessive mechanical loading promotes osteoarthritis through the gremlin-1-NF-κB pathway.
Song Ho ChangDaisuke MoriHiroshi KobayashiYoshifumi MoriHideki NakamotoKeita OkadaYuki TaniguchiShurei SugitaFumiko YanoUng-Il ChungJoo-Ri Kim-KaneyamaMotoko YanagitaAris EconomidesErnesto CanalisDi ChenSakae TanakaTaku SaitoPublished in: Nature communications (2019)
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.
Keyphrases
- nuclear factor
- reactive oxygen species
- transcription factor
- rheumatoid arthritis
- botulinum toxin
- signaling pathway
- weight gain
- cell death
- stem cells
- knee osteoarthritis
- extracellular matrix
- type diabetes
- skeletal muscle
- cell proliferation
- metabolic syndrome
- lps induced
- genome wide
- physical activity
- wild type
- dna methylation
- bone mineral density
- dna binding
- genome wide identification
- postmenopausal women
- solar cells