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

Area of Science:

• Biochemistry
• Cell Biology
• Orthopedics

Background:

• Osteoarthritis pathogenesis is linked to excessive mechanical loading of articular cartilage.
• Chondrocytes are key cells in cartilage homeostasis and response to mechanical stress.

Purpose of the Study:

• To identify novel molecular factors involved in the pathogenesis of osteoarthritis induced by mechanical loading.
• To elucidate the role of gremlin-1 in chondrocyte response to mechanical stress and its contribution to osteoarthritis.

Main Methods:

• Investigated gremlin-1 expression in chondrocytes under mechanical loading (cyclic strain, hydrostatic pressure).
• Utilized mouse models with intra-articular gremlin-1 antibody administration or chondrocyte-specific Gremlin-1 deletion.
• Assessed activation of nuclear factor-κB (NF-κB) signaling and reactive oxygen species (ROS) production.
• Examined the effect of gremlin-1 on anabolic gene expression (Sox9, Col2a1, Acan).

Main Results:

• Gremlin-1 is induced by mechanical loading in chondrocytes, particularly in deeper cartilage layers.
• Gremlin-1 activates NF-κB signaling, leading to increased catabolic enzyme production.
• Inhibition of gremlin-1 (antibody or genetic deletion) decelerated osteoarthritis development in mice.
• Mechanical loading-induced ROS production, mediated by ras-related C3 botulinum toxin substrate 1, activates RelA/p65, which upregulates Gremlin-1.
• Gremlin-1 antagonizes bone morphogenetic protein-induced expression of anabolic genes.

Conclusions:

• Gremlin-1 is a critical mediator of cartilage degeneration in response to excessive mechanical loading.
• Gremlin-1 promotes an osteoarthritis-promoting catabolic environment by activating NF-κB and inhibiting anabolic pathways.
• Targeting gremlin-1 presents a potential therapeutic avenue for mitigating osteoarthritis progression.