Emerging regulators of the inflammatory process in osteoarthritis

Abstract

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'.

Conflict of interest statement

Competing interests: R.T. declares he serves as a Scientific Advisory Board Member for Cardax.

Figures

Figure 1. Relationships between inflammatory mediator networks in OA

This schematic illustrates how several of the different classes of inflammatory mediators, including PRRs and their DAMP ligands, conventional inflammatory cytokines, and activated complement proteins C5a and C5b-9 network to augment meniscal fibrocartilage and articular cartilage damage in early and progressive OA. These mediators promote macroscopic inflammation, including synovitis, and can drive cartilage matrix catabolism, but some also promote cartilage remodelling and repair. The number and diversity of inflammatory mediators in OA joints, the paradoxical roles of some of these moieties in tissue damage and repair, and the physiological roles of some mediators in host defense, means targeting individual mediators for OA therapy is difficult. Abbreviations: COMP, cartilage oligomeric matrix protein; DAMP, danger associated molecular pattern; HMGB1, high mobility group box protein 1; LMW-HA, low molecular weight hyaluronan; MAC, membrane attack complex; OA, osteoarthritis; PRR, pattern recognition receptor; RAGE, receptor for advanced glycation endproducts; TGF-β, transforming growth factor β; TLR, Toll-like receptor.

Figure 2. Functions of AMPK and SIRT1 in chondrocyte resistance to cell stress and inflammatory processes that promote matrix catabolism

AMPK, which has multiple endogenous and exogenous activators, promotes activation of SIRT1. LKB1 is the primary upstream kinase that promotes AMPK activity, and decreased LKB1 increases chondrocyte matrix procatabolic responses to IL-1β and TNF. Active LKB1 and AMPK are decreased in OA, injured, and ageing chondrocytes. AMPK and SIRT1 exert anti-inflammatory effects, including inhibition of NFκB activation via SIRT1, which deacetylates the p65 subunit of NFκB and thereby primes p65 for proteasomal degradation; these effects limit chondrocyte matrix procatabolic responses. In addition, AMPK and SIRT1 promote autophagy, with attendant repair of damaged organelles, such as mitochondria and ER, and AMPK and SIRT1 inhibit ER stress, providing further means to limit inflammation in OA cartilage. Abbreviations: AMPK, 5′-AMP-activated protein kinase; ER, endoplasmic reticulum; LKB1, liver protein kinase B1; SIRT1, NAD-dependent protein deacetylase sirtuin-1.

Figure 3. Modulation of inflammatory processes by the UPR in chondrocytes in OA

The UPR signalling cascades triggered by dissociation of the chaperone GRP78 from the ER transmembrane proteins PERK, IRE1, and ATF6, and activated by biomechanical injury, nitric oxide, and certain inflammatory mediators. Alternatively spliced, transcriptionally activated XBP1 (XBP1s) promotes chondrocyte maturation to procatabolic hypertrophic differentiation, mediated in part by cross-talk with the ATF6 pathway. XBP1s also drives matrix pro-catabolic responses in response to IL-1β, as does excess CHOP, another terminal UPR effector. CHOP also promotes chondrocyte superoxide production and apoptosis. Knock-out of CHOP is chondroprotective in mouse knee instability-induced OA in vivo. Abbreviations: ATF6, activating transcription factor 6; CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; GRP78, 78 kDa glucose-regulated protein; IRE1, inositol-requiring protein 1; PERK, protein kinase RNA-like ER kinase; UPR, unfolded protein response; XBP1, X-box-binding protein 1; XBP1s, X-box-binding protein 1 splicing form.

Figure 4. Therapeutic modulation of AMPK and SIRT1 as an Entry Point for “Stop Signals” for Chondrocyte Pro-Catabolic Reprogramming by Inflammation, Oxidative Stress, and Altered UPR and Autophagy

The Figure schematizes the proposal that the bio-energy sensors AMPK and SIRT1 can be an integrative entry point to therapeutic suppression (red lines) of the inflammatory process-mediated re-programming of chondrocytes to a pro-catabolic state. In this manner, there is potential to slow the progression of OA, but this question needs direct testing in vivo.