Knee loading reduces MMP13 activity in the mouse cartilage

Abstract

BackgroundModerate loads with knee loading enhance bone formation, but its effects on the maintenance of the knee are not well understood. In this study, we examined the effects of knee loading on the activity of matrix metalloproteinase13 (MMP13) and evaluated the role of p38 MAPK and Rac1 GTPase in the regulation of MMP13.MethodsKnee loading (0.5–3 N for 5 min) was applied to the right knee of surgically-induced osteoarthritis (OA) mice as well as normal (non-OA) mice, and MMP13 activity in the femoral cartilage was examined. The sham-loaded knee was used as a non-loading control. We also employed primary non-OA and OA human chondrocytes as well as C28/I2 chondrocyte cells, and examined MMP13 activity and molecular signaling in response to shear at 2–20 dyn/cm2.ResultsDaily knee loading at 1 N for 2 weeks suppressed cartilage destruction in the knee of OA mice. Induction of OA elevated MMP13 activity and knee loading at 1 N suppressed this elevation. MMP13 activity was also increased in primary OA chondrocytes, and this increase was attenuated by applying shear at 10 dyn/cm2. Load-driven reduction in MMP13 was associated with a decrease in the phosphorylation level of p38 MAPK (p-p38) and NFκB (p-NFκB). Molecular imaging using a fluorescence resonance energy transfer (FRET) technique showed that Rac1 activity was reduced by shear at 10 dyn/cm2 and elevated by it at 20 dyn/cm2. Silencing Rac1 GTPase significantly reduced MMP13 expression and p-p38 but not p-NFκB. Transfection of a constitutively active Rac1 GTPase mutant increased MMP13 activity, while a dominant negative mutant decreased it.ConclusionsKnee loading reduces MMP13 activity at least in part through Rac1-mediated p38 MAPK signaling. This study suggests the possibility of knee loading as a therapy not only for strengthening bone but also preventing tissue degradation of the femoral cartilage.

Rac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development

“…Valve remodeling and development is regulated by coordinated actions between matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motifs families of zinc metalloproteinases . Studies have shown a role for Rac1 in the regulation of extracellular matrix degradation along with matrix metalloproteinase expression and activity . The thickened Rac1 SHF aortic valve leaflets along with decreased valve cell density and increased deposition of glycosaminoglacans observed in this study strongly suggest defects in valvular extracellular matrix degradation and remodeling.…”

Low-Intensity Pulsed Ultrasound Affects Chondrocyte Extracellular Matrix Production via an Integrin-Mediated p38 MAPK Signaling Pathway

“…On the other hand, in adult articular tissues, p38 is known to play an important role in the inflammatory process (Joos et al 2009), and some evidence suggests that p38 is a major signaling molecule in the induction of MMP-13 and the activity of p38 can have negative effects on cartilage matrix maintenance (Julovi et al 2011;Mengshol et al 2000;Pei et al 2006). In addition, moderate mechanical stress such as knee loading reduces MMP-13 activity through the p38 MAPK signaling pathway in normal articular cartilage (Hamamura et al 2013). Therefore, we speculated that LIPUS inhibited phosphorylation of p38 in OA chondrocytes, but facilitated phosphorylation of p38 in normal chondrocytes to promote adaptation to a moderate mechanical stress.…”

Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

“…Mechanical loading and joint health have a unique relationship. Low levels of mechanical loading, such as mild exercise, can benefit cartilage by preventing injury‐induced cartilage degradation, maintaining thicker cartilage, and increasing proteoglycan synthesis . However, higher levels of loading can lead to cartilage degradation by decreasing proteoglycan synthesis, inducing chondrocyte apoptosis, and rupturing critical stabilizing ligaments .…”