Knee loading reduces MMP13 activity in the mouse cartilage

Kazunori Hamamura, Ping Zhang, Liming Zhao, Joon W. Shim, Andy Chen, Todd R. Dodge, Qiaoqiao Wan, Han Shih, Sungsoo Na, Chien Chi Lin, Hui (Herb) Sun, Hiroki Yokota

Research output: Contribution to journalArticle

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Abstract

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/cm§ssup§2§esup§. 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/ cm§ssup§2§esup§. 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§ssup§2§esup§ and elevated by it at 20 dyn/cm§ssup§2§esup§. 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.

Original languageEnglish (US)
Article number312
JournalBMC Musculoskeletal Disorders
Volume14
DOIs
StatePublished - 2013

Fingerprint

Cartilage
Knee
Osteoarthritis
GTP Phosphohydrolases
p38 Mitogen-Activated Protein Kinases
Chondrocytes
Thigh
Fluorescence Resonance Energy Transfer
Molecular Imaging
Knee Osteoarthritis
Osteogenesis
Transfection
Maintenance
Phosphorylation
Bone and Bones

Keywords

  • Cartilage
  • Chondrocyte
  • Knee loading
  • MMP13
  • Osteoarthritis
  • Rac1

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Rheumatology

Cite this

Hamamura, K., Zhang, P., Zhao, L., Shim, J. W., Chen, A., Dodge, T. R., ... Yokota, H. (2013). Knee loading reduces MMP13 activity in the mouse cartilage. BMC Musculoskeletal Disorders, 14, [312]. https://doi.org/10.1186/1471-2474-14-312

Knee loading reduces MMP13 activity in the mouse cartilage. / Hamamura, Kazunori; Zhang, Ping; Zhao, Liming; Shim, Joon W.; Chen, Andy; Dodge, Todd R.; Wan, Qiaoqiao; Shih, Han; Na, Sungsoo; Lin, Chien Chi; Sun, Hui (Herb); Yokota, Hiroki.

In: BMC Musculoskeletal Disorders, Vol. 14, 312, 2013.

Research output: Contribution to journalArticle

Hamamura, K, Zhang, P, Zhao, L, Shim, JW, Chen, A, Dodge, TR, Wan, Q, Shih, H, Na, S, Lin, CC, Sun, HH & Yokota, H 2013, 'Knee loading reduces MMP13 activity in the mouse cartilage', BMC Musculoskeletal Disorders, vol. 14, 312. https://doi.org/10.1186/1471-2474-14-312
Hamamura, Kazunori ; Zhang, Ping ; Zhao, Liming ; Shim, Joon W. ; Chen, Andy ; Dodge, Todd R. ; Wan, Qiaoqiao ; Shih, Han ; Na, Sungsoo ; Lin, Chien Chi ; Sun, Hui (Herb) ; Yokota, Hiroki. / Knee loading reduces MMP13 activity in the mouse cartilage. In: BMC Musculoskeletal Disorders. 2013 ; Vol. 14.
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abstract = "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/cm§ssup§2§esup§. 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/ cm§ssup§2§esup§. 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§ssup§2§esup§ and elevated by it at 20 dyn/cm§ssup§2§esup§. 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.",
keywords = "Cartilage, Chondrocyte, Knee loading, MMP13, Osteoarthritis, Rac1",
author = "Kazunori Hamamura and Ping Zhang and Liming Zhao and Shim, {Joon W.} and Andy Chen and Dodge, {Todd R.} and Qiaoqiao Wan and Han Shih and Sungsoo Na and Lin, {Chien Chi} and Sun, {Hui (Herb)} and Hiroki Yokota",
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AU - Hamamura, Kazunori

AU - Zhang, Ping

AU - Zhao, Liming

AU - Shim, Joon W.

AU - Chen, Andy

AU - Dodge, Todd R.

AU - Wan, Qiaoqiao

AU - Shih, Han

AU - Na, Sungsoo

AU - Lin, Chien Chi

AU - Sun, Hui (Herb)

AU - Yokota, Hiroki

PY - 2013

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N2 - 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/cm§ssup§2§esup§. 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/ cm§ssup§2§esup§. 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§ssup§2§esup§ and elevated by it at 20 dyn/cm§ssup§2§esup§. 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.

AB - 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/cm§ssup§2§esup§. 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/ cm§ssup§2§esup§. 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§ssup§2§esup§ and elevated by it at 20 dyn/cm§ssup§2§esup§. 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.

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KW - Chondrocyte

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KW - Osteoarthritis

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