A new review published in The Journal of Bone & Joint Surgery lays out how osteoarthritis develops at the molecular level and which disease-modifying treatments are closest to being implemented in practices and clinics.
The review, published online Oct. 15, was written by Alexander Meininger, MD, of Steamboat Orthopaedic & Spine Institute in Steamboat Springs, Colo., and Hasan Baydoun, MD, of Mubadala Health – HealthPoint in Abu Dhabi, United Arab Emirates.
The authors say the future of osteoarthritis care lies in matching patients to therapies by disease endotype, such as inflammatory, metabolic, mechanical or senescence-driven, and they identify posttraumatic arthritis as an optimal setting for early disease interception, according to a report shared with Becker’s.
Here are 10 things to know from the review:
- The authors say osteoarthritis is no longer best understood as passive “wear and tear.” They describe a biologically dynamic disease in which cartilage cells, synovial tissue, subchondral bone and the immune system feed a self-amplifying cycle of tissue destruction.
- Current management is limited to symptom relief, according to the authors. Nonsteroidal anti-inflammatory drugs reduce pain without changing disease progression, intra-articular corticosteroid injections give temporary relief but may accelerate cartilage loss, and total joint arthroplasty treats end-stage disease at a cost the authors put above $60 billion a year in the U.S.
- Cellular aging appears to be an early driver, not just a late consequence. The review says declining autophagy, the process cartilage cells use to clear damaged components, precedes cell death. It also cites mouse studies in which clearing senescent cells attenuated osteoarthritis after an anterior cruciate ligament injury, and transplanting senescent cells into knees was enough to induce an osteoarthritis-like condition.
- Blocking a single inflammatory signal has not worked well. Systemic interleukin-1 (IL-1) blockade with anakinra produced disappointing results in clinical trials, which the authors attribute to redundancy among inflammatory pathways. They say that has pushed development toward broader downstream targets and local delivery.
- The authors argue osteoarthritis should be considered a disease of dysregulated immune homeostasis, not simply mechanical overload. They point to pro-inflammatory macrophages and T cell subsets in the synovium and to impaired regulatory T cells.
- Among disease-modifying drugs, the intra-articular Wnt pathway inhibitor lorecivivint showed improvements in pain and medial joint-space width versus placebo in a phase 2 evaluation. The fibroblast growth factor 18 (FGF-18) analog sprifermin produced dose-dependent gains in cartilage thickness on MRI in the phase 2 FORWARD trial, though the authors say the link between structural gains and symptoms remains debated. Anti-nerve growth factor antibodies relieved pain but raised safety concerns over rapidly progressive osteoarthritis requiring joint replacement.
- Senolytics have had a mixed record. The dasatinib-plus-quercetin combination cleared senescent cells in mice and human cartilage samples, and clinical trials of the dietary flavonoid fisetin in knee osteoarthritis remain active. But UBX0101, a locally delivered senolytic, failed its primary end point of pain reduction against placebo in a phase 2 trial.
- Intra-articular gene therapy aims to avoid repeated injections by having joint cells make a therapeutic protein continuously. In a first-in-human phase 1 trial of GNSC-001, which encodes the IL-1 receptor antagonist, nine patients received escalating doses with no serious adverse events, and the protein stayed elevated in synovial fluid for more than 13 months. A phase 1b trial of 67 participants confirmed 12-month safety, and the therapy has FDA Fast Track and Regenerative Medicine Advanced Therapy designations, with a pivotal phase 2b/3 trial anticipated for 2026, the authors write.
- Other gene therapy programs have had mixed results. PCRX-201, from Pacira BioSciences, showed sustained improvements in pain and knee function scores at three years after a single injection, and dosing began in April 2025 in a phase 2 trial. XT-150, a plasmid-based IL-10 therapy, did not meet its primary end point in a phase 2 trial of 289 patients.
- The CARTISTEM stem cell product, made from umbilical cord blood, has the most extensive clinical evidence among allogeneic cell therapies, the review says. In a phase 3 trial of 114 patients, 97.7% of the CARTISTEM group versus 71.7% of the microfracture group improved by at least one cartilage repair grade at 48 weeks, though clinical scores did not differ significantly at that point. By 60 months, the CARTISTEM group had significantly better pain and function scores, according to the review. The authors note most evidence comes from South Korean populations, the procedure generally requires a mini-arthrotomy and a 12-week partial-weight-bearing protocol, and it costs more than microfracture. A U.S. phase 3 trial is underway.
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