Hand Osteoarthritis: Molecular Mechanisms, Randomized Controlled Trials, and the Future of Targeted Treatment

Abstract

Hand osteoarthritis (OA) is a prevalent and disabling condition, yet its pathogenesis remains less studied than OA in large weight-bearing joints. Emerging genetic, epigenetic, and microbiome research suggests that hand OA might be biologically distinct, involving joint-specific pathways not shared by knee or hip OA. This review integrates genome-wide association studies specific to hand OA, highlighting key molecular contributors such as inflammatory cytokines. These genetic insights, together with emerging data on epigenetic alterations and gut microbial dysbiosis, point to broader systemic and regulatory influences on hand OA onset and progression. We also assess pharmacologic interventions tested in randomized controlled trials that have attempted to target these pathways. While agents such as TNF and IL-6 inhibitors, hydroxychloroquine, and corticosteroids have shown limited success, emerging evidence supports the potential of methotrexate in synovitis-positive general hand OA, platelet-rich plasma in thumb carpometacarpal (CMC) OA, and prolotherapy in interphalangeal (IP) OA. These findings illustrate the persistent gap between mechanistic understanding and therapeutic success. Future work must prioritize multifactorial strategies for addressing pain and translational frameworks that link molecular mechanisms to treatment response. In summary, this review offers an update on hand OA and identifies key opportunities for more targeted and effective therapy.

Keywords: DNA methylation; adipokines; epigenetics; genetic variants; gut–joint axis; hand osteoarthritis; inflammatory cytokines; microbiome dysbiosis; randomized controlled trials; thumb CMC osteoarthritis.

Figure 1

TNF-α-driven inflammatory pathways in joint degradation. TNF-α activates IL-1β signaling while inhibiting the chondroprotective IL-4 pathway, leading to cartilage degradation (MMPs, ADAMTS4), chemokine production (CCL2, CCL5), immune cell recruitment, and NF-κB-mediated transcription of inflammatory genes.

Figure 2

Adipokine-driven inflammation linking obesity to hand OA. Adipokines such as resistin and chemerin from adipose tissue trigger systemic inflammation via upregulation of TNF-α, TLR4, IL-6, and MAPK/ERK pathways, promoting joint inflammation and the development of hand OA.

Figure 3

Dual roles of YAP/TAZ in fibroblast-like synoviocytes (FLSs) and mesenchymal stem cells (MSCs) in cartilage regulation. In FLSs, YAP/TAZ activation promotes MMP-1 and MMP-13 expression in response to TNF-α and IL-1β, driving ECM degradation. Conversely, in MSCs, YAP/TAZ–TEAD signaling enhances chondrogenesis by counteracting NF-κB signaling, thereby supporting cartilage repair and regeneration.

Figure 4

The gut–joint axis in hand OA. Bilophila spp. and Desulfovibrio spp. promote inflammation via cytokine induction and NF-κB activation, while Roseburia spp. counteract inflammation through Treg-mediated anti-inflammatory pathways.