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Article Open Access

Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study

  • Authors:
    • Xiao Ma
    • Jingjing Ma
    • Han Zhang
    • Xiaodong Jia
    • Tianrui Wang
    • Shanshan Ma
    • Yingze Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Orthopaedics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266075, P.R. China, Institute of Infectious Disease, Radiation Oncology Center, The Fifth Medical Center of People's Liberation Army General Hospital, Beijing 100071, P.R. China, Department of Gynecological Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233099, P.R. China
    Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 4
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    Published online on: October 21, 2025
       https://doi.org/10.3892/etm.2025.12999
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Abstract

Uterine fibroids (UFs) are benign smooth‑muscle tumors of the uterus that commonly affect women of reproductive age and can influence systemic hormonal and inflammatory states. Osteoarthritis (OA) is a chronic degenerative disease of weight‑bearing joints (e.g., hip and knee) and a leading cause of pain and disability. Shared hormonal and immune pathways plausibly link UFs and OA; however, whether a genetic or biological association exists remains unclear. The present study utilized Mendelian randomization (MR) analysis combined with experimental validation to investigate a potential genetic and biological association between UF and OA in weight‑bearing joints. Bidirectional MR analyses were carried out using a genome‑wide association study to evaluate the potential genetic association between UFs, hip OA (hOA) and knee OA (kOA). The primary method used in the present study was inverse variance weighting, which was supported by complementary approaches including weighted median and MR‑Egger. Heterogeneity and pleiotropy were assessed using the Cochran's Q test, MR‑Egger intercept and MR‑pleiotropy residual sum and outlier. Additionally, sensitivity analyses were conducted using leave‑one‑out analysis. Furthermore, experimental validation was carried out using a Transwell co‑culture system to investigate the effects of UF cells (UFCs) on OA chondrocytes. MR analysis revealed a significant inverse genetic association between UFs and the risk of hOA. However, no genetic association was observed between UFs and kOA. Reverse MR analyses did not support a genetic association between hOA or kOA with UF. Furthermore, experimental results demonstrated that UFCs significantly mitigated OA cartilage degeneration by inhibiting the degradation of Collagen II and Aggrecan at the mRNA level. The present study indicated a potential novel genetic association between UF and hOA, suggesting a potential biological association likely mediated by the tumor microenvironment (such as hormonal or immune alterations), which warrants further mechanistic investigation.
View Figures

Figure 1

Procedure for the bidirectional MR
analysis. (A) Underlying principle of MR analysis. A-1) Correlation
hypothesis: IVs exhibited a correlation with the exposure. A-2)
Independence hypothesis: IVs were not associated with confounders
(such as the body mass index and age). A-3) Exclusive hypothesis:
Selected IVs were not directly engaged in the outcome except via
the exposure route. (B) The process of bidirectional MR in the
present study. MR, Mendelian Randomization; IVs, instrumental
variables; SNP, single nucleotide polymorphism; hOA, hip
osteoarthritis; kOA, knee osteoarthritis; IVW, inverse variance
weighted.

Figure 2

Genetic associations between UF and
hOA. (A) Scatter plots, (B) forest plots and (C) leave-one-out
sensitivity analysis for the estimated genetic association of UF on
hOA. (D) Scatter plots, (E) forest plots and (F) leave-one-out
sensitivity analysis for estimated genetic association of hOA on
UF. UF, uterine fibroids; hOA, hip osteoarthritis; SNP, single
nucleotide polymorphism; MR, Mendelian Randomization.

Figure 3

Genetic associations between UF and
kOA. (A) Scatter plots, (B) forest plots and (C) leave-one-out
sensitivity analysis for the estimated genetic association of UF on
kOA. (D) Scatter plots, (E) forest plots and (F) leave-one-out
sensitivity analysis for estimated genetic association of kOA on
UF. UF, uterine fibroids; kOA, knee osteoarthritis; SNP, single
nucleotide polymorphism; MR, Mendelian Randomization.

Figure 4

Potential role of UFCs in OA
chondrocyte degeneration. (A) A schematic diagram of the
experimental procedure. (B) Cell viabilities of OA chondrocytes and
OA chondrocytes co-cultured with UFCs were assessed using Cell
Counting Kit-8 assays after 24 h with absorbance measured at 450
nm. (C) mRNA levels of Collagen II were measured using reverse
transcription-quantitative PCR. (D) mRNA levels of Aggrecan were
measured using reverse transcription-quantitative PCR. (E) Live
(green)/dead (red) staining of OA chondrocytes or OA chondrocytes
co-cultured with UFCs after 24 h using a Calcein AM/PI kit. Scale
bar, 1,000 µm. (F) The number of live/dead IL-1β-induced
chondrocytes or IL-1β-induced chondrocytes co-cultured with UFCs
were measured using a Calcein AM/PI kit, analyzed with Image-Pro
6.0 and quantified. In all experiments, n=3. *P<0.05.
UFC, uterine fibroid cells; OA, osteoarthritis; ns, not
significant.
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Copy and paste a formatted citation
Spandidos Publications style
Ma X, Ma J, Zhang H, Jia X, Wang T, Ma S and Zhang Y: Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study. Exp Ther Med 31: 4, 2026.
APA
Ma, X., Ma, J., Zhang, H., Jia, X., Wang, T., Ma, S., & Zhang, Y. (2026). Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study. Experimental and Therapeutic Medicine, 31, 4. https://doi.org/10.3892/etm.2025.12999
MLA
Ma, X., Ma, J., Zhang, H., Jia, X., Wang, T., Ma, S., Zhang, Y."Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study". Experimental and Therapeutic Medicine 31.1 (2026): 4.
Chicago
Ma, X., Ma, J., Zhang, H., Jia, X., Wang, T., Ma, S., Zhang, Y."Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study". Experimental and Therapeutic Medicine 31, no. 1 (2026): 4. https://doi.org/10.3892/etm.2025.12999
Copy and paste a formatted citation
x
Spandidos Publications style
Ma X, Ma J, Zhang H, Jia X, Wang T, Ma S and Zhang Y: Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study. Exp Ther Med 31: 4, 2026.
APA
Ma, X., Ma, J., Zhang, H., Jia, X., Wang, T., Ma, S., & Zhang, Y. (2026). Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study. Experimental and Therapeutic Medicine, 31, 4. https://doi.org/10.3892/etm.2025.12999
MLA
Ma, X., Ma, J., Zhang, H., Jia, X., Wang, T., Ma, S., Zhang, Y."Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study". Experimental and Therapeutic Medicine 31.1 (2026): 4.
Chicago
Ma, X., Ma, J., Zhang, H., Jia, X., Wang, T., Ma, S., Zhang, Y."Investigating the association between uterine fibroids and weight‑bearing joint osteoarthritis based on a bidirectional Mendelian randomization study". Experimental and Therapeutic Medicine 31, no. 1 (2026): 4. https://doi.org/10.3892/etm.2025.12999
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