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BMC Musculoskeletal Disorders

, 14:312

Clinical rheumatology and osteoporosis


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-cm.

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-cm. 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-cm and elevated by it at 20 dyn-cm. 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.

KeywordsKnee loading Cartilage Chondrocyte Osteoarthritis MMP13 Rac1 AbbreviationsADAMTSA disintegrin and metalloproteinase with thrombospondin motifs

BMCBone mineral content

BMDBone mineral density

CFPCyan fluorescent protein

FRETFluorescence resonance energy transfer

MAPKMitogen-activated protein kinase

MMP13Matrix metalloproteinase 13

NFκBNuclear factor kappa B


YFPYellow fluorescent protein.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2474-14-312 contains supplementary material, which is available to authorized users.

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Autor: Kazunori Hamamura - Ping Zhang - Liming Zhao - Joon W Shim - Andy Chen - Todd R Dodge - Qiaoqiao Wan - Han Shih - Sungso


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