Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. Age and joint injury are among the primary risk factors for OA development. Since many Veterans are older and/or had traumatic joint injury when in service, they are at high risk to develop OA. However, there are yet no effective medical therapies to delay and/or limit OA development and progression, and this is an urgent medical need. Progressive degeneration of articular cartilage is a major characteristic of the disease. Chondrocyte, the only cell type residing in the cartilage matrix, regulate the homeostatic balance between matrix synthesis and degradation, which fails in OA. Thus, one approach to rationally designed new OA therapies is to improve chondrocyte function by targeting pathogenesis of the disease. AMP-activated protein kinase (AMPK) is a super-regulator of energy homeostasis and cellular metabolism. We recently discovered that AMPK activity is constitutively present in normal articular chondrocytes, but is decreased in OA chondrocytes, correlated with increased catabolic responses. In addition, loss of AMPK activity in chondrocytes is associated with inflammation, biomechanical injury and aging. Moreover, pharmacologic activation of AMPK not only attenuates pro-catabolic responses to inflammatory cytokines and biomechanical injury, but also promotes mitochondrial biogenesis and protects chondrocytes from oxidative stress. Furthermore, in our preliminary in vivo studies, we observed that berberine, a natural plant product used as traditional medicine and dietary supplement, and known to active AMPK, significantly limits mice from development of knee OA induced by surgical destabilization of medial meniscus (DMM). Building on these findings, we propose to test our central hypotheses that sustained AMPK activity is critical to articular cartilage homeostasis and that AMPK is a potential interventional target to delay and/or limit the onset and progression of OA. We specifically aim to: (1) Define how AMPK activation is chondroprotective in vitro at the molecular level. (2) Determine if reduced AMPK activity in human knee articular cartilage, particularly in the superficial zone where cartilage degeneration appears to be initiated in OA, is a fundamental change in normal aging, providing a platform for OA development and progression. (3) Test the hypothesis that molecularly selective loss of AMPK activity promotes OA development and progression in mice in vivo (4) Test the translational hypothesis that therapeutic induction of AMPK activity by the highly selective AMPK activator A-769662 delays and/or limits the development and progression of spontaneous OA in vivo using the STR/ort mice (an established model for spontaneous OA that resembles human OA). Completion of these studies will provide new insights into how changes in chondrocyte bio-energetics affects cartilage homeostasis, and aid to develop a new therapeutic approach by targeting at AMPK to suppress the development and progression of OA.

Public Health Relevance

Osteoarthritis (OA) is the most common form of arthritis, and an enormous and expensive public health problem. There are yet no medical therapies (disease modifying OA drugs (DMOADS)) to prevent or effectively slow the primary disease process. Age and joint injury are the two major risk factors for OA development. Veterans are at high risk to develop OA as many are older and/or had traumatic joint injury when they were in and after service. Thus, the unmet medical need for new and effective therapeutics for OA is particularly urgent for the special needs of the health care of Veterans. Completion of these studies will potentially provide a novel approach to protect cartilage degradation by targeted activation of AMPK, thereby to prevent and therapeutically slow OA development and progression.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Immunology A (IMMA)
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VA San Diego Healthcare System
San Diego
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Chen, Liang-Yu; Lotz, Martin; Terkeltaub, Robert et al. (2018) Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes. J Biol Chem 293:12259-12270
Serrano, Ramon L; Chen, Liang-Yu; Lotz, Martin K et al. (2018) Impaired Proteasomal Function in Human Osteoarthritic Chondrocytes Can Contribute to Decreased Levels of SOX9 and Aggrecan. Arthritis Rheumatol 70:1030-1041
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