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.
Highlights
Moderate loads with knee loading enhance bone formation, but its effects on the maintenance of the knee are not well understood
We demonstrated that loading to the knee of non-OA and OA mice reduced activities of collagenases, gelatinases, and matrix metalloproteinase13 (MMP13) in the femoral cartilage
Using C28/I2 chondrocyte cells, we have shown that silencing Rac1 by siRNA reduces the activation of p38 Mitogenactivated protein kinase (MAPK), which is reported to be linked to the upregulation of MMP13 by inflammatory cytokines [13,29] and in osteosarcomas [30]
Summary
Moderate loads with knee loading enhance bone formation, but its effects on the maintenance of the knee are not well understood. Moderate mechanical loading applied laterally to the knee has been shown to enhance bone formation [1] and attenuate pain perception-linked signaling [2], but the effect of lateral loads to the knee on the maintenance of cartilage tissues remains undetermined [3]. The loading force required to stimulate bone formation due to knee loading is lower than that of other mechanical loading regimens, and strains in areas of bone formation are reduced. This characteristic makes knee loading an attractive potential treatment in accelerating fracture repair [1]. Loads are directly applied to the knee, loading effects on maintenance of cartilage tissue and chondrocytes have not been examined
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