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AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice.

ABSTRACT: Osteoarthritis (OA) is a progressive degenerative disease of the joints that is associated with both joint injury and ageing. Here, we investigated the role of the energy sensor AMP-activated protein kinase (AMPK) in maintaining a healthy state of articular cartilage and in OA development. Using cartilage-specific, tamoxifen-inducible AMPK?1 conditional knockout (AMPK?1 cKO), AMPK?2 conditional knockout (AMPK?2 cKO) and AMPK?1?2 conditional double knockout (AMPK? cDKO) mice, we found that compared with wild-type (WT) littermates, mutant mice displayed accelerated severity of surgically induced OA, especially AMPK? cDKO mice. Furthermore, male but not female AMPK? cDKO mice exhibited severely spontaneous ageing-associated OA lesions at 12 months of age. The chondrocytes isolated from AMPK? cDKO mice resulted in an enhanced interleukin-1? (IL-1?)-stimulated catabolic response. In addition, upregulated expression of matrix metalloproteinase-3 (MMP-3), MMP-13 and phospho-nuclear factor-?B (phospho-NF-?B) p65 and increased levels of apoptotic markers were detected in the cartilage of AMPK? cDKO mice compared with their WT littermates in vivo. Thus, our findings suggest that AMPK activity in chondrocytes is important in maintaining joint homeostasis and OA development.

SUBMITTER: Zhou S

PROVIDER: S-EPMC5320548 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice.

Zhou Sheng S Lu Wanli W Chen Liang L Ge Qiting Q Chen Dongyang D Xu Zhihong Z Shi Dongquan D Dai Jin J Li Jianxin J Ju Huangxian H Cao Yi Y Qin Jinzhong J Chen Shuai S Teng Huajian H Jiang Qing Q

Scientific reports 20170222

Osteoarthritis (OA) is a progressive degenerative disease of the joints that is associated with both joint injury and ageing. Here, we investigated the role of the energy sensor AMP-activated protein kinase (AMPK) in maintaining a healthy state of articular cartilage and in OA development. Using cartilage-specific, tamoxifen-inducible AMPKα1 conditional knockout (AMPKα1 cKO), AMPKα2 conditional knockout (AMPKα2 cKO) and AMPKα1α2 conditional double knockout (AMPKα cDKO) mice, we found that compar ...[more]

PMID: 28225087

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Project description:RUNX2 is a transcription factor critical for chondrocyte maturation and normal endochondral bone formation. It promotes the expression of factors catabolic to the cartilage extracellular matrix and is upregulated in human osteoarthritic cartilage and in murine articular cartilage following joint injury. To date, in vivo studies of RUNX2 overexpression in cartilage have been limited to forced expression in osteochondroprogenitor cells preventing investigation into the effects of chondrocyte-specific RUNX2 overexpression in postnatal articular cartilage. Here, we used the Rosa26Runx2 allele in combination with the inducible Col2a1CreERT2 transgene or the inducible AcanCreERT2 knock-in allele to achieve chondrocyte-specific RUNX2 overexpression (OE) during embryonic development or in the articular cartilage of adult mice, respectively. RUNX2 OE was induced at embryonic day 13.5 (E13.5) for all developmental studies. Histology and in situ hybridization analyses suggest an early onset of chondrocyte hypertrophy and accelerated terminal maturation in the limbs of the RUNX2 OE embryos compared to control embryos. For all postnatal studies, RUNX2 OE was induced at 2 months of age. Surprisingly, no histopathological signs of cartilage degeneration were observed even 6 months following induction of RUNX2 OE. Using the meniscal/ligamentous injury (MLI), a surgical model of knee joint destabilization and meniscal injury, however, we found that RUNX2 OE accelerates the progression of cartilage degeneration following joint trauma. One month following MLI, the numbers of MMP13-positive and TUNEL-positive chondrocytes were significantly greater in the articular cartilage of the RUNX2 OE joints compared to control joints and 2 months following MLI, histomorphometry and Osteoarthritis Research Society International (OARSI) scoring revealed decreased cartilage area in the RUNX2 OE joints. Collectively, these results suggest that although RUNX2 overexpression alone may not be sufficient to initiate the OA degenerative process, it may predetermine the rate of OA onset and/or progression following traumatic joint injury. © 2019 American Society for Bone and Mineral Research.

Dataset Information

AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice.

Publications

AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice.

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