AMPK: implications in osteoarthritis and therapeutic targets

Abstract

Osteoarthritis (OA) is the most common skeletal disease and the leading cause of pain and disability in the aged population (>65 years). However, the underlying factors involved in OA pathogenesis remain elusive which has resulted in failure to identify disease-modifying OA drugs. Altered metabolism has been shown to be a prominent pathological change in OA. As a critical bioenergy sensor, AMP-activated protein kinase (AMPK) mediates not only energy homeostasis but also redox balance in chondrocytes to counter various cell stress. Dysfunction of AMPK activity has been associated with reduced autophagy, impaired mitochondrial function, excessive reactive oxygen species generation, and inflammation in joint tissue. These abnormalities ultimately trigger articular cartilage degeneration, synovial inflammation, and abnormal subchondral bone remodeling. This review focuses on recent findings describing the central role of AMPK in joint homeostasis and OA development. We also highlight current advances that target AMPK as a novel therapeutic strategy for OA prevention.

Keywords: AMPK; Osteoarthritis; autophagy; inflammation; metabolism.

Figure 1

Mechanisms modulating AMP-activated protein kinase (AMPK) activity. AMPK consists of α, β, and γ subunits. There are two distinct ways to trigger AMPK activation. i): AMP and ADP bind to the γ subunits and allosterically activate AMPK; ii) Phosphorylation of Thr172 in the α subunit by upstream kinases such as liver kinase B1 (LKB1), calcium-calmodulin-dependent kinase 2 (CaMKK2), and transforming growth factor-β-activated protein kinase-1 (TAK1) induces the activation of AMPK. AMPK is dephosphorylated by protein phosphatase (PP) thereby being inhibited. Moreover, ATP can also oppose the activation of AMPK by inhibiting the γ subunits that are dependent on allosteric activation and phosphorylating the LKB1-induced α subunit.

Figure 2

Dysfunction of AMPK activity disrupts cartilage, synovium and subchondral bone homeostasis, thus contributing to OA development. Aging, low-grade inflammation, mechanical injury, and metabolic syndromes result in compromised AMPK activity. Impaired AMPK activity decreases the level and activity of SIRT1, PGC-1α, FoXO3a, TSC2, and ULK-1 which causes mitochondrial dysfunction, aggravates oxidative stress, attenuates autophagy, and increases inflammation-mediated cartilage catabolism. On the contrary, expression of p-P65, p-mTOR1, CHOP, and c-Fos are up-regulated which promotes several signaling pathways, including NF-κB, ER stress, and osteoclastogenesis, resulting in chondrocyte apoptosis, synovial inflammation, and abnormal subchondral bone remodeling. Targeting impaired AMPK activity (e.g. AMPK pharmacological activators, natural herbs, metformin, and appropriate exercise) would be a potential approach to prevent OA.