Knee loading reduces MMP13 activity in the mouse cartilage

BMC Musculoskeletal Disorders

Hiroki Yokota²  Hui Bin Sun¹  Chien-Chi Lin³  Sungsoo Na³  Han Shih³  Qiaoqiao Wan³  Todd R Dodge³  Andy Chen³  Joon W Shim³  Liming Zhao³  Ping Zhang⁴  Kazunori Hamamura³ 

[1]Department of Orthopaedic Surgery, Albert Einstein College of Medicine, Bronx, NY 10461, USA

[2]Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

[3]Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, SL220C, 723 West Michigan Street, Indianapolis, IN 46202, USA

[4]School of Basic Medical Sciences, Tianjin Medical University, Tanjin 300070, People’s Republic of China

关键词: Rac1;    MMP13;    Osteoarthritis;    Chondrocyte;    Cartilage;    Knee loading;   

Others  :  1129242
DOI  :  10.1186/1471-2474-14-312

 received in 2013-07-03, accepted in 2013-10-18,  发布年份 2013

【 摘 要 】

Background

Moderate 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.

Methods

Knee 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.

Results

Daily 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.

Conclusions

Knee 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.

【 授权许可】

   
2013 Hamamura et al.; licensee BioMed Central Ltd.

【 图 表 】

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