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Review
. 2025;3(1):15.
doi: 10.1038/s44294-025-00063-1. Epub 2025 Feb 25.

The intersection of aging and estrogen in osteoarthritis

Aysegul Atasoy-Zeybek  1 , Kelly K Showel  1   2 , Christopher V Nagelli  1   3 , Jennifer J Westendorf  3 , Christopher H Evans  1
Affiliations
Review

The intersection of aging and estrogen in osteoarthritis

Aysegul Atasoy-Zeybek et al. NPJ Womens Health. 2025.

Abstract

Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, inflammation, and pain. While multiple factors contribute to OA development, age and sex are primary risk factors, particularly affecting postmenopausal women. The dramatic increase in OA risk after menopause suggests estrogen deficiency accelerates disease progression. This review explores the molecular mechanisms connecting aging and estrogen deficiency in OA development, focusing on key genes and pathways identified through RNA sequencing.

Keywords: Biological therapy; Diseases; Physiology.

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Conflict of interest statement

Competing interestsThe authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Illustration of the distinct differences between a healthy joint and an osteoarthritic joint.
In the healthy joint, young chondrocytes maintain the extracellular matrix composed of collagen type -1, -2, proteoglycans (aggrecan, decorin, biglycan, fibromodulin, lumican), and glycoproteins (cartilage oligomeric matrix protein). The articular surface is smooth and intact, with a highly organized matrix structure and no signs of inflammation. The osteoarthritic joint displays senescent chondrocytes with increased expression of transcription factors including cyclin-dependent kinase inhibitor 2 A (p16ink4a), tumor protein p53 (p53), cyclin-dependent kinase inhibitor 1 A (p21cip1) and reactive oxygen species. The senescence-associated secretory phenotype (SASP) factors are elevated, including interleukins -1, -6, -7, -8, -17 (IL -1, -6, -7, -8, -17), tumor necrosis factor alpha (TNFα), granulocyte-macrophage colony-stimulating factor (GM-CSF), matrix metalloproteinase -1, -3, -10, -13, -19 (MMP -1, -3, -10, -13, -19), A Disintegrin and Metalloproteinase with Thrombospondin Motifs -4, -5, -8 (ADAMTS -4, -5, -8); C-C Motif Chemokine Ligand -2, -3, -4, -5, -8 (Ccl -2, -3, -4, -5, -8) C-X-C Motif Chemokine Ligand -5, -9, -13 (Cxcl -5, -9, -13). These molecular changes lead to alterations in cartilage, including changes in chondrocyte phenotype, matrix degradation, cartilage loss, and inflammation-associated aging.
Fig. 2
Fig. 2. The role of estrogen-related receptors (ERRs) in chondrocyte proliferation and cartilage degradation during aging and menopause.
Aging and menopause lead to disruption of estrogen related receptors alpha (ERRα) and gamma (ERRγ) signaling. Interleukin 1 Beta (IL-1β) stimulation activates ERRα through the prostaglandin E2/cyclic adenosine monophosphate/protein kinase A (PGE2/cAMP/PKA) pathway, resulting in increased matrix metalloproteinase-13 (MMP-13) production. Conversely, ERRα promotes chondrocyte proliferation via SRY-box transcription factor 9 (Sox-9) upregulation. Overexpression of ERRγ regulates interleukin 6 (IL-6) signaling and cause increased production of MMP-9, leading to molecular dysfunction, disrupted homeostasis, and subsequent cartilage degradation. Elevated levels of ERRγ lead to the upregulation of MMP-3 and MMP-13, contributing to the breakdown of cartilage matrix.
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