Recent research has increasingly focused on the biological and molecular processes associated with knee osteoarthritis, particularly within the context of post-menopausal women. The prevalence of this condition is notably higher among women than men, especially after menopause, indicating a significant interplay between hormonal changes and joint health.

A Centuries-Old Observation

Historically, the relationship between menopause and osteoarthritis has been acknowledged, as evidenced by the observations of English physician John Haygarth in 1805:

“The nodosities [irregularities] of the joint are almost peculiar to women and begin when the menses naturally cease.”

This quote underscores the long-standing recognition of this issue, yet contemporary research often overlooks knee osteoarthritis in post-menopausal females despite it being a well-established risk factor for the condition [2], [3], [4]. This study aims to bridge that gap by focusing specifically on post-menopausal models.

Mimicking Human Menopause

In the quest to investigate knee osteoarthritis related to menopause, researchers employed various methods to simulate menopause in mice, which do not experience a natural menopausal transition like humans. One conventional method, ovariectomy (surgical removal of the ovaries), has limitations as it does not reflect the gradual hormonal changes experienced during the human menopause transition. Instead, researchers utilized a novel approach involving the chemical induction of menopause using 4-vinylcyclohexene diepoxide (VCD). This method allows for the preservation of ovarian function and mimics the natural perimenopausal period, providing a more relevant model for study.

Declining Joint Health

In their experiments, researchers assessed the health of crucial components of the knee joint, including cartilage, subchondral bone, and the synovium. Initial assessments, conducted 11 days post-VCD injection, showed no significant differences in these components between the menopause and non-menopause groups. However, as the study progressed, notable degradation in cartilage was observed in the menopause group, alongside a deterioration of synovial health. Analyses indicated that while some areas of the subchondral bone remained healthy, others exhibited significant declines in both volume and density in menopausal mice.

Modeling the Molecular Changes

To delve deeper into the molecular underpinnings of their observations, researchers utilized mass spectrometry to identify protein changes in cartilage samples from various stages of menopause. Their findings highlighted significant alterations in cellular signaling pathways associated with the menopausal transition:

  1. Increased susceptibility to collagen degradation.
  2. Changes in extracellular matrix (ECM) composition.
  3. Impacted cellular senescence and actin cytoskeleton integrity.

Additionally, they employed simulation systems to predict the effects of restoring sex hormone levels and administering senolytics on joint health. The combination of 17β-estradiol and progesterone was shown to reverse several adverse processes in joints.

Testing the Predictions

Subsequent in vivo tests were conducted where mice induced into menopause received treatments with either 17β-estradiol, progesterone, or both. Results demonstrated that while cartilage integrity improved in the treatment groups, synovial and subchondral bone tissues showed no significant changes. Behavioral assessments further indicated that hormonal treatments improved step length but had mixed results on stride length.

Improved Chondrocyte Health

The outcomes prompted researchers to explore human-derived chondrocytes isolated from post-menopausal knee surgery patients. When cultured with the same hormones and dasatinib, these cells displayed:

  • Decreased expression of senescence markers.
  • Increased proliferation markers.
  • Enhanced chondrogenic gene expression.

These results fortified their hypothesis that restoring hormonal balance during menopause aids in mitigating the detrimental effects of aging on cartilage cells, emphasizing the critical role of hormonal signaling in joint health.

Restoring Health with Hormones

This pivotal study establishes a connection between hormonal changes during menopause and the development of knee osteoarthritis in post-menopausal women. By restoring hormones like 17β-estradiol and progesterone, there is potential for the improvement of cartilage and overall joint health. Future research will be crucial in determining whether such hormone replacement therapies could benefit women afflicted with knee osteoarthritis.

Literature Cited

  • [1] Gilmer, G., et al. (2025). Menopause-induced 17β-estradiol and progesterone loss increases senescence markers, matrix disassembly and degeneration in mouse cartilage. Nature Aging, 5(1), 65–86.
  • [2] Prieto-Alhambra, D., et al. (2014). Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Annals of the Rheumatic Diseases, 73(9), 1659–1664.
  • [3] Hame, S. L., & Alexander, R. A. (2013). Knee osteoarthritis in women. Current Reviews in Musculoskeletal Medicine, 6(2), 182–187.
  • [4] Srikanth, V. K., et al. (2005). A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis. Osteoarthritis and Cartilage, 13(9), 769–781.