Abstract
Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity.
Highlights
It has been shown that scavengers of reactive oxygen species (ROS), such as N-acetyl cysteine (NAC), inhibit or reduce the extent of Heme oxygenase-1 (HO-1) induction by oxidative stress [81]. These results indicate that intracellular ROS plays an important role in HMOX1 gene expression regulation: free heme produced in response to oxidative stress is catabolized into a non-cytotoxic catabolite because oxidative stress is coupled to the induction of HO-1 [82]
Given that the induction of HO-1 is tied to extracellular stimuli, its upstream mitogen-activated protein kinase (MAPK) signaling cascades such as extracellular signal-regulated kinase (ERK), c-Jun terminal kinase (JNK), and p38 MAPK are known to play a significant role in mediating gene expression [83,84,85,86,87]
Contemporary surgical options, therecontemporary are no clinically available drugs that delay onset or the progression of the
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Oxidative stress-related imbalances between the production of ROS and the antioxidant capacity of joint cells such as chondrocytes and synovial fibroblasts has been identified as a major component of OA progression [5,7,8,9,10]. Contemporary studies, including those from our group, reported that genetically or chemically-induced antioxidant signals prevent cartilage degeneration and OA severity in aging and surgically-induced OA models [11,12,13,14,15]. We describe the most up-to-date information relating to the relationship between HO-1 activity and OA pathogenesis, and discuss the findings of drug treatment studies centered around OA prevention via HO-1 induction
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