High follicle‐stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF‐κB pathway

Liu, Yaping; Zhang, Mengqi; Kong, Dehuan; Wang, Yan; Li, Jian; Liu, Wenjuan; Fu, Ying; Xu, Jin

doi:10.1002/2211-5463.12975

Cited by 2 publications

(2 citation statements)

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“…These effects were quantified by effect size, betweenness (i.e., capacity of a protein to communicate with distant proteins( 59 )), and centroid (i.e., probability of a protein to be functionally capable of organizing downstream proteins( 59 )) ( Figure S4C-E ). Although many studies have implied that loss of estradiol( 42, 60–62 ) and heightened FSH levels( 63–65 ) may drive KOA, these findings implicate a previously unrecognized role of disrupted progesterone, relaxin, and LH signaling in mediating cartilage homeostasis.…”

Section: Resultsmentioning

confidence: 91%

A network medicine approach to elucidate mechanisms underlying menopause-induced knee osteoarthritis

Gilmer

Iijima

Jackson

et al. 2023

Preprint

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Post-menopausal women present with the highest incidence and morbidity of knee osteoarthritis (KOA), but no disease-modifying therapies are available. This treatment gap may be driven by the absence of menopause in preclinical studies, as rodents do not naturally maintain a menopausal phenotype. Here, we employed a chemically-induced menopause model to map the trajectory of KOA at the tissue and proteome levels and test therapeuticsin silico. Middle-aged female mice were randomized to sesame oil (non-menopause) or 4-vinycyclohexene diepoxide (menopause) injections. Following comprehensive validation of our model, knees were collected across perimenopause and menopause for histology, and cartilage samples were micro-dissected for mass spectrometry proteomics. Menopause mice displayed aggravated cartilage degeneration and synovitis relative to non-menopause mice. An unbiased pathway analysis revealed progesterone as a predominant driver of pathological signaling cascades within the cartilage proteome. Network medicine-based analyses suggested that menopause induction amplifies chondrocyte senescence, actin cytoskeleton-based stress, and extracellular matrix disassembly. We then usedin silicodrug testing to evaluate how restoration of sex hormones impacted the cartilage network. The greatest restoration was observed with combined estradiol/progesterone treatment (i.e., hormone therapy), althoughin silicotreatment with a senolytic drug also partially recovered the cartilage proteome. Taken together, our findings using a translatable female aging model demonstrate that menopausal aging induces progressive cartilage degeneration and amplifies age-related synovitis. These changes may be driven by a previously unappreciated role of progesterone loss and menopause-induced cellular senescence. Lastly,in silicotreatment suggests an estradiol/progesterone cocktail or senolytics may attenuate menopause-induced cartilage pathology.One Sentence SummaryMenopause induces cartilage degradation, senescence, and extracellular matrix disassembly, while hormone therapy restores the cartilage proteome.

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Section: Resultsmentioning

confidence: 91%

A network medicine approach to elucidate mechanisms underlying menopause-induced knee osteoarthritis

Gilmer

Iijima

Jackson

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…It is plausible that single hormones, such as PDGF and follicle-stimulating hormone (FSH), among others, which become elevated with age, have ubiquitous functions. High serum FSH levels, for example, associate not only with bone loss, but also with obesity, hyperlipidemia, osteoarthritis, and neurodegeneration (17)(18)(19)(20). Likewise, play a shift from contractile to a dedifferentiated, synthetic phenotype, resulting in intimal and medial thickening, elevated collagen/elastin ratio in the arterial wall, and increased mechanical vessel rigidity and stiffness (14).…”

Section: Discussionmentioning

confidence: 99%