Emerging role of metabolic signaling in synovial joint remodeling and osteoarthritis

Abstract

Obesity and associated metabolic diseases collectively referred to as the metabolic syndrome increase the risk of skeletal and synovial joint diseases, including osteoarthritis (OA). The relationship between obesity and musculoskeletal diseases is complex, involving biomechanical, dietary, genetic, inflammatory, and metabolic factors. Recent findings illustrate how changes in cellular metabolism and metabolic signaling pathways alter skeletal development, remodeling, and homeostasis, especially in response to biomechanical and inflammatory stressors. Consequently, a better understanding of the energy metabolism of diarthrodial joint cells and tissues, including bone, cartilage, and synovium, may lead to new strategies to treat or prevent synovial joint diseases such as OA. This rationale was the basis of a workshop presented at the 2016 Annual ORS Meeting in Orlando, FL on the emerging role of metabolic signaling in synovial joint remodeling and OA. The topics we covered included (i) the relationship between metabolic syndrome and OA in clinical and pre-clinical studies; (ii) the effect of biomechanical loading on chondrocyte metabolism; (iii) the effect of Wnt signaling on osteoblast carbohydrate and amino acid metabolism with respect to bone anabolism; and (iv) the role of AMP-activated protein kinase in chondrocyte energetic and biomechanical stress responses in the context of cartilage injury, aging, and OA. Although challenges exist for measuring in vivo changes in synovial joint tissue metabolism, the findings presented herein provide multiple lines of evidence to support a central role for disrupted cellular energy metabolism in the pathogenesis of OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2048-2058, 2016.

Keywords: bone; cartilage; metabolic syndrome; obesity; osteoarthritis.

Figure 1

Effect of obesity versus joint injury on the lifetime risk of developing symptomatic knee OA. Obesity, defined as a body mass index ≥ 30, doubles the risk of knee OA compared to normal weight or underweight individuals (body mass index < 25). The effect of obesity on knee OA risk is similar to that for a prior joint injury (60.5% versus 56.8%, respectively). ∞P<0.0001, comparison with normal weight and obese. #P=0.01, comparison with overweight and obese. *P=0.002, comparison of prior joint injury (no and yes). Figure produced from data reported in [2].

Figure 2

Association of metabolic syndrome components and OA pathology in men and women. A. Metabolic syndrome components as defined by the National Cholesterol Education Program Adult Treatment Panel III and updated by the American Heart Association. Metabolic syndrome is diagnosed as ≥ 3 of these conditions. B. Prevalence of individual metabolic syndrome components in men and women diagnosed with metabolic syndrome. Pink boxes indicated significantly higher prevalence in women, and blue boxes indicated higher prevalence in men. Data from [36]. C. Sex-biases in OA pathology and metabolic syndrome related factors (pink = female, blue = male). References for these relationships are provided in the text.

Figure 3

Model of mechanically-induced changes in chondrocyte energy metabolism. As a source of energy, glucose metabolism begins with glycolysis. Glycolysis can route energy to the pentose phosphate pathway (PPP) to make 5-membered sugars including nucleic acids. In the presence of oxygen, the tri-carboxylic acid (TCA) cycle can increase the yield of ATP compared with glycolysis alone. Glucose is also be used to make amino acid precursors for protein synthesis. In both cartilage explants and 3D cultured chondrocytes, physiological loading (blue) appears to stimulate the TCA cycle, while high-magnitude injurious loading (red) increases oxidative stress [62, 68, 69]. Studies have used small molecule inhibitors, including rotenone, oligomycin, and N-acetylcystein (NAC) to modulate metabolic and oxidative processes.

Figure 4

AMPK as a potential therapeutic target for OA. Aging, joint injury, and low-grade inflammation impair AMPK activity in articular cartilage, causing dysregulation of AMPK signaling in articular chondrocytes. This would result in mitochondrial dysfunction (e.g., reduced capacity of mitochondrial biogenesis), increased oxidative stress and inflammation-mediated matrix catabolism, and poor cellular quality control (e.g., increased ER stress and decreased autophagy). All of which can compromise cell survival and cartilage tissue integrity, ultimately leading to OA development and progression. However, targeted activation of AMPK (potentially achieved by pharmacological approach, natural plant products or dietary restriction) could be an attractive therapeutic strategy for OA.