Challenges and opportunities of pharmacological interventions for osteoarthritis: A review of current clinical trials and developments

Vrouwe, J.P.M.; Burggraaf, Jacobus; Kloppenburg, Margreet; Stuurman, Frederik E.

doi:10.1016/j.ocarto.2021.100212

Cited by 10 publications

(6 citation statements)

References 96 publications

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“…The existing OA pharmaceutical therapies have no discernible disease-modifying impact. In order to discover innovative, disease-modifying OA drugs to enhance patients’ quality of life, a new age of research must be launched exploring new targets (Vrouwe et al 2021 ). As a result, the current study assessed the anti-inflammatory effects of probenecid and/or l-carnitine in attenuating OA via modulating the miR-373/P2X7/NLRP3/NF-kB cue.…”

Section: Discussionmentioning

confidence: 99%

L-Carnitine augments probenecid anti-inflammatory effect in monoiodoacetate-induced knee osteoarthritis in rats: involvement of miRNA-373/P2X7/NLRP3/NF-κB milieu

Mahfouz,

H. El-Rewini,

I. Ghoneim

et al. 2023

Inflammopharmacol

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Osteoarthritis (OA) is a degenerative joint disease, whereas the underlying molecular trails involved in its pathogenesis are not fully elucidated. Hence, the current study aimed to investigate the role of miRNA-373/P2X7/NLRP3/NF-κB trajectory in its pathogenesis as well as the possible anti-inflammatory effects of probenecid and l-carnitine in ameliorating osteoarthritis via modulating this pathway. In the current study, male Sprague Dawley rats were used and monoiodoacetate (MIA)-induced knee osteoarthritis model was adopted. Probenecid and/or L-carnitine treatments for 21 days succeeded in reducing OA knee size and reestablishing motor coordination and joint mobility assessed by rotarod testing. Moreover, different treatments suppressed the elevated serum levels of IL-1β, IL-18, IL-6, and TNF-α via tackling the miRNA-373/P2X7/NLRP3/NF-κB, witnessed as reductions in protein expressions of P2X7, NLRP3, cleaved caspase-1 and NF-κB. These were accompanied by increases in procaspase-1 and IκB protein expression and in miRNA-373 gene expression OA knee to various extents. In addition, different regimens reversed the abnormalities observed in the H and E as well as Safranin O-Fast green OA knees stained sections. Probenecid or l-carnitine solely showed comparable results on the aforementioned parameters, whereas the combination therapy had the most prominent effect on ameliorating the aforementioned parameters. In conclusion, l-carnitine augmented the probenecid’s anti-inflammatory effect to attenuate MIA-induced osteoarthritis in rats by provoking the miRNA-373 level and inhibiting the P2X7/NLRP3/NF-κB milieu, leading to the suppression of serum inflammatory cytokines: IL-1β, IL-18, IL-6, and TNF-α. These findings suggest the possibility of using probenecid and l-carnitine as a useful therapeutic option for treatment of osteoarthritis. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

L-Carnitine augments probenecid anti-inflammatory effect in monoiodoacetate-induced knee osteoarthritis in rats: involvement of miRNA-373/P2X7/NLRP3/NF-κB milieu

Mahfouz,

H. El-Rewini,

I. Ghoneim

et al. 2023

Inflammopharmacol

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“…In considering the significant socio-economic and medical importance of OA, numerous ways to improve pharmacological interventions are being investigated with the goals of reducing disease progression and pain in patients with OA, including immunomodulators targeting synovitis and pain [65]. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach regarding these goals [66].…”

Section: Discussionmentioning

confidence: 99%

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis

Rošin,

Kelam,

Jurić

et al. 2024

IJMS

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The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans’ heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

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“…The results of phase 2 and 3 clinical trials for osteoarthritis were recently summarized in a detailed review by Vrouwe et al in December of 2021 [53] in which they focused on various treatment targets for osteoarthritis, including inflammation-related targets. Since publication of that review, a few additional clinical trials have been approved and are recruiting.…”

Section: Therapeutic Approaches To Targeting Inflammation In Osteoart...mentioning

confidence: 99%

Inflammation in osteoarthritis: the latest progress and ongoing challenges

Knights¹,

Redding²,

Maerz

2022

Current Opinion in Rheumatology

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Purpose of reviewThe understanding of inflammation in osteoarthritis is rapidly evolving. This review highlights important basic science, mechanistic, and clinical findings since 2020 that underscore the current notion of osteoarthritis as an inflammatory disease.Recent findingsThere exists a disconnect between clinical radiographic findings and patient symptoms in osteoarthritis. Inflammation, in particular synovitis, has been put forward as a potential explanation for this disconnect. New findings have shed light on the temporal dynamics and activation states of joint-resident or systemically derived immune cell populations, notably macrophages, that participate in the inflammatory response. The intricate crosstalk in which they engage may underpin disparate pain and symptoms in patients, for instance during osteoarthritis flares. The role of biological and environmental factors such as exercise, age, and diet, have been the subject of recent studies for their protective or destructive roles in osteoarthritis inflammation. Despite these advances, no disease-modifying osteoarthritis treatments targeting inflammation have emerged.SummaryOsteoarthritis is a debilitating chronic disease that manifests with widely varying symptomatology. Inflammation is now appreciated as a key pathophysiological process in osteoarthritis, but there remain considerable gaps in our understanding of its role in disease progression and how best to target the inflammatory response for therapeutic interventions.

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Challenges and opportunities of pharmacological interventions for osteoarthritis: A review of current clinical trials and developments

Cited by 10 publications

References 96 publications

L-Carnitine augments probenecid anti-inflammatory effect in monoiodoacetate-induced knee osteoarthritis in rats: involvement of miRNA-373/P2X7/NLRP3/NF-κB milieu

L-Carnitine augments probenecid anti-inflammatory effect in monoiodoacetate-induced knee osteoarthritis in rats: involvement of miRNA-373/P2X7/NLRP3/NF-κB milieu

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis

Inflammation in osteoarthritis: the latest progress and ongoing challenges

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