Home›Genetics & Precision Medicine› Observational transcriptomic analysis identifies genes associated with knee osteoarthritis severity in older adults
Observational transcriptomic analysis identifies genes associated with knee osteoarthritis severity in older adultsKnee Pain Could Start in Your Thigh Muscles, Study Says
medRxivPublished April 23, 2026Study authors: Evans, D. S.; Mansfield, T. A.; Many, G. M.; Sagendorf, T. J.; Farsijani, S.; Goodpaster, B. H.; Spa…DOI ↗Editorial oversight: Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development
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Key Takeaway
Consider that muscle transcriptomic associations with knee OA severity are observational and not causal.
This is an observational study from the Study of Muscle, Mobility and Aging (SOMMA) that performed bulk RNA sequencing on vastus lateralis muscle from 523 older adults with knee radiographs. The analysis compared gene expression in participants with radiographic knee osteoarthritis (OA) (Kellgren-Lawrence grade ≥2, n=197; grade ≥3, n=112) to a control group (grade ≤1, n=326).
The authors identified 27 genes associated with KL ≥2 OA and 41 genes associated with KL ≥3 OA, all at a false discovery rate (FDR) ≤0.05. Sixteen genes were significantly associated in both severity contrasts, including BDNF and IRF2; for 15 of these genes, the association magnitude was larger with more severe OA (KL ≥3). Gene set enrichment analysis indicated pathways involving DNA repair and branched-chain amino acid (BCAA) catabolism were enriched in both OA severity groups.
Key limitations noted by the authors include the observational design, which precludes causal inference, and the need for longitudinal studies to determine how these genes affect knee OA progression. The study population was limited to older adults, and findings may not generalize to other age groups.
Practice relevance is restrained; the findings generate hypotheses about molecular pathways in knee OA but do not support any clinical intervention. The results are based on observational data, and certainty is not quantified.
Why the muscle matters more
Knee osteoarthritis affects millions of people around the world. It makes simple tasks like walking or standing very hard. Doctors usually focus on the joint, but the muscle around it might be key.
For years, experts believed arthritis was just about worn-down cartilage. They thought the joint was the only place to look for answers. But here is the twist.
What the genes actually do
This new study suggests the muscle tissue is talking to the joint. It changes how the body feels pain when the knee is damaged. This connection was not understood until now.
Think of your body like a complex communication network. Nerves send signals between your muscles and your joints constantly. When the muscle changes, it might tell the joint to hurt more.
What scientists didn’t expect
Researchers looked at 523 older adults in the SOMMA study. They took muscle samples and X-rays of the knees. Then they checked the genetic code inside the muscle cells.
The study found 41 genes linked to severe knee damage. These genes were more active when arthritis was worse. Some genes were involved in how the body feels pain.
This doesn’t mean this treatment is available yet.
Is this ready for clinics?
Experts say this shifts how we see joint pain. It suggests muscle health is tied to joint health. We cannot ignore the tissue surrounding the bone.
You cannot change your genes today. But this research helps doctors understand the disease better. Talk to your doctor about muscle strength for knee support.
This study looked at a snapshot in time. We do not know if these genes cause the pain or result from it. More time is needed to track changes.
Scientists will run more tests to confirm these links. Future trials might test if strengthening muscles changes these genes. Approval for new therapies is still years away.
Objectives. The association between skeletal muscle gene expression and knee osteoarthritis (OA) was examined among older adult participants of the Study of Muscle, Mobility and Aging (SOMMA). Methods. Inclusion criteria included knee radiographs and bulk RNA sequencing (RNAseq) in vastus lateralis muscle, resulting in 523 participants (56% female). Radiographic knee OA was determined by Kellgren-Lawrence (KL) grades. Differential gene expression was analyzed using a control group (KL [≤] 1, n = 326) and two nested case groups: (a) KL [≥] 2 (n = 197), (b) KL [≥] 3 (n = 112). Results. Compared with controls, there were 27 and 41 genes associated (FDR [≤] 0.05) with KL [≥] 2 and KL [≥] 3, respectively, and 16 genes significantly associated in both contrasts. For 15 of the 16 genes, the association magnitude was larger with more severe OA (KL [≥] 3). Genes associated in both contrasts included brain-derived neurotrophic factor (BDNF) and interferon regulatory factor-2 (IRF2). Gene sets enriched in KL [≥] 2 and KL [≥] 3 contrasts included DNA repair and branched chain amino acid (BCAA) catabolism. Conclusions. Our results in older adult SOMMA participants indicate that knee OA is associated with genes and pathways expressed in skeletal muscle that are involved in pain sensitization, BCAA catabolism, muscle function preservation, calcium transport and storage, inflammation, and extracellular matrix remodeling. Additional longitudinal studies will be needed to determine how these genes could affect the progression of knee OA.
