Emerging regulators of the inflammatory process in osteoarthritis.

Chronic, low-grade inflammation in osteoarthritis (OA) contributes to symptoms and disease progression. Effective disease-modifying OA therapies are lacking, but better understanding inflammatory pathophysiology in OA could lead to transformative therapy. Networks of diverse innate inflammatory danger signals, including complement and alarmins, are activated in OA. Through inflammatory mediators, biomechanical injury and oxidative stress compromise the viability of chondrocytes, reprogramming them to hypertrophic differentiation and proinflammatory and pro-catabolic responses. Integral to this reprogramming are 'switching' pathways in transcriptional networks, other than the well-characterized effects of NFκB and mitogen-activated protein kinase signalling; HIF-2α transcriptional signalling and ZIP8-mediated Zn(2+) uptake, with downstream MTF1 transcriptional signalling, have been implicated but further validation is required. Permissive factors, including impaired bioenergetics via altered mitochondrial function and decreased activity of bioenergy sensors, interact with molecular inflammatory responses and proteostasis mechanisms such as the unfolded protein response and autophagy. Bioenergy-sensing by AMPK and SIRT1 provides 'stop signals' for oxidative stress, inflammatory, and matrix catabolic processes in chondrocytes. The complexity of molecular inflammatory processes in OA and the involvement of multiple inflammatory mediators in tissue repair responses, raises daunting questions about how to therapeutically target inflammatory processes and macroscopic inflammation in OA. Bioenergy sensing might provide a pragmatic 'entry point'.