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

Developers

Sheng Zhou, Wanli Lu, Liang Chen, Qing Jiang et al.

Description of the technology

Osteoarthritis is a progressive degenerative disease of the joints that is associated with both joint injury and ageing. Multiple lines of evidence have suggested that the energy sensor − AMP-activated protein kinase (AMPK) − could be a promising therapeutic target for osteoarthritis given that AMPK activation in chondrocytes led to anti-catabolic and anti-apoptotic effects in vitro, and AMPK imparts protection in an osteoarthritis animal model. Moreover, decreased AMPK activity was also detected in osteoarthritis cartilage. Therapies targeting AMPK are a good strategy for osteoarthritis therapy and they are attracting increasing attention. However, there is still a lack of genetic evidence to understand the accurate role of AMPK in the homeostasis of adult articular cartilage.

The developers of this technology investigated the role of AMPK in maintaining a healthy state of articular cartilage and in osteoarthritis development. Using cartilage-specific, tamoxifen-inducible AMPKα1 conditional knockout (AMPKα1 cKO), AMPKα2 conditional knockout (AMPKα2 cKO) and AMPKα1α2 conditional double knockout (AMPKα cDKO) mice, they found that compared with wild-type littermates, mutant mice displayed accelerated severity of surgically induced osteoarthritis, especially AMPKα cDKO mice. Furthermore, male but not female AMPKα cDKO mice exhibited severely spontaneous ageing-associated osteoarthritis lesions at 12 months of age. The chondrocytes isolated from AMPKα cDKO mice resulted in an enhanced interleukin-1β-stimulated catabolic response. In addition, upregulated expression of matrix metalloproteinase-3 (MMP-3), MMP-13 and phospho-nuclear factor-κB (phospho-NF-κB) p65 and increased levels of apoptotic markers were detected in the cartilage of AMPKα cDKO mice compared with their wild-type littermates in vivo. Thus, the findings suggest that AMPK activity in chondrocytes is important in maintaining joint homeostasis and osteoarthritis development.

Practical application

Thus, the study, supporting this technology, demonstrated that cartilage-specific deletion of AMPKα during the adult stage resulted in accelerated osteoarthritis progression in a mouse model. Given that pharmacological activators, nutraceuticals, caloric restriction diets and exercise activate AMPK, future research, based on this technology results, directed on promoting AMPK activity in cartilage will lead to novel and effective therapeutic strategies for osteoarthritis.

Laboratories

• Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing (China)
• Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University Nanjing (China)
• State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University Nanjing (China)

Links

Publications

• Zhou, Sh. et al. «AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice." 7 Scientific Reports (2017): 43245.
• Cai, D. et al. «Histone deacetylase inhibition activates Nrf2 and protects against osteoarthritis." 17 Arthritis Res. Ther. (2015): 269.