7% of the global population suffers from osteoarthritis with women and old age people being more at risk.
Osteoarthritis (OA) is the most prevalent arthritic disease affecting millions. It is a degenerative disease affecting the entire joint structure, including the articular cartilage, synovium, tendons, etc. Common clinical features are pain, joint dysfunction, and deformity. Risk factors include aging, obesity, prior joint injuries, and certain genetic and biomechanical predisposing factors.
Low-grade inflammation in joints plays a critical role in OA pathogenesis
Low-grade inflammation appears at an early stage of OA and is generally chronic and primarily involves the innate immune response (reviewed in 1). Synovitis, characterized by synovial inflammation is common in OA and is associated with increased severity of symptoms. Macrophages in OA joints produce pro-inflammatory mediators including cytokines and growth factors through multiple signalling pathways. Damaged tissue products in OA joints can bind and activate pattern-recognition receptors and the complement system in macrophages and mast cells. These activations promote NF-kB expression, which triggers autocrine production of cytokines (TNFa, IL-1b), eventually resulting in the synthesis of more inflammatory mediators, e.g., matrix metalloproteinase (MMPs).
Comparison of inflammatory mediators between arthritic diseases
Synovitis is common in both OA and rheumatoid arthritis (RA), the prototypical inflammatory arthritis. Targeting the key mediators of RA inflammation, such as TNFa, IL-1b, and NF-kB has been proven to improve inflammation in RA indicating that similar strategies may result in successful OA therapies. To be noted, inflammation and macrophage biology slightly differ in OA. For example, unlike in RA, IL-1b expression does not depend on TNFa in OA and NF-kB plays a more important role in RA. These differences in mediators and their level suggest further evaluation of these treatments in controlling OA inflammation.
Potential therapies and their limitation
Approved OA therapies target symptoms of advanced disease stages, such as pain control with analgesics, non-steroidal anti-inflammatory drugs, steroids and viscosupplementation with hyaluronic acid. Joint replacement is considered the last resource. Thus, anti-inflammatory therapeutics to prevent or delay disease progression at early-stage OA require consideration. Several therapeutics that showed positive results in RA patients and OA murine models did not yield similar results in OA patients (Reviewed in 1,2).
Potential therapeutics show non-conclusive results in OA patients
Anti-TNFa antibodies have shown promising results in a large cohort of inter-phalangeal OA patients but did not show considerable improvement in two other studies of 10 and 12 patients, respectively. Similarly, inhibiting IL-1β showed improvements in some studies while partial or no damage reduction in others. Therapies inhibiting MMPs in humans lacked efficacy. Clinical trials targeting various growth factors that hold potential for maintaining cartilage or facilitating its repair are ongoing.
Combination therapy may offer improved efficacy
Due to the multifactorial and heterogenic nature of OA, effective treatment might require a combination of approaches. Careful selection of broad but selective targeting is needed for better efficacy and reduced toxicity. The low efficacy of anti-inflammatory therapies in human trials suggests that targeting a single cytokine at the systemic level is not enough to reduce damage. Combination therapy inhibiting both IL-1b and TNFa has shown higher efficacy than individual therapies.
Limitation of proposed therapies
OA can affect several joints and crosstalk between these joints through soluble mediators is assumed. However, most systemic therapies show toxicity and can increase infection risk. Local growth factor therapy risks promoting osteophyte outgrowth, whereas systemic diffusion of the growth factor might induce abnormal growth. Note, combination therapies are not recommended for RA due to their toxicity. Therefore, minimizing side effects is a major challenge for the effective use of anti-inflammatory therapies.
| Key points — Inflammation plays a critical role in OA pathogenesis. — Effective inhibitors of inflammation make promising therapeutic candidates. — Therapies blocking TNFa, IL-1b, MMPs, and growth factors need further evaluation in clinical trials. — Optimizing combinatorial approaches may provide high efficacy and low toxicity. |
Conclusion
Understanding molecular pathways of inflammation, the signature molecules during OA progression, and their presentation in large vs small joints will help to develop specific OA therapies. More studies and clinical trials are needed for a comprehensive evaluation of anti-inflammatory therapies.
References
1. Robinson WH, Lepus CM, Wang Q, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(10):580-592. doi:10.1038/nrrheum.2016.136
2. Bondeson J, Blom AB, Wainwright S, Hughes C, Caterson B, van den Berg WB. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62(3):647-657. doi:10.1002/art.27290