Uncovering the “riddle of femininity” in osteoarthritis: a systematic review and meta-analysis of menopausal animal models and mathematical modeling of estrogen treatment

Gilmer, Gabrielle; Bean, Allison; Iijima, Hirotaka; Jackson, Natalie; Thurston, Rebecca C.; Ambrosio, Fabrisia

doi:10.1016/j.joca.2022.12.009

Cited by 7 publications

(4 citation statements)

References 86 publications

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“…On the one hand, estrogen treatment at higher doses (>500 μg·kg −1 per day) has been shown to be more effective at reversing cartilage degeneration than treatment at lower doses (<500 μg·kg −1 per day). 214 On the other hand, excess levels of estrogen can lead to autoimmune diseases and cancer, especially breast cancer. 200 Further studies are needed to clarify the optimal threshold level of estrogen dosage and the biological mechanisms that drive these positive and/or negative changes, some of which appear to strongly depend on the level of estrogen.…”

Section: Controversial Results and Risks Associated With Estrogen Tre...mentioning

confidence: 99%

Low back pain and osteoarthritis pain: a perspective of estrogen

et al. 2023

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Low back pain (LBP) is the world’s leading cause of disability and is increasing in prevalence more rapidly than any other pain condition. Intervertebral disc (IVD) degeneration and facet joint osteoarthritis (FJOA) are two common causes of LBP, and both occur more frequently in elderly women than in other populations. Moreover, osteoarthritis (OA) and OA pain, regardless of the joint, are experienced by up to twice as many women as men, and this difference is amplified during menopause. Changes in estrogen may be an important contributor to these pain states. Receptors for estrogen have been found within IVD tissue and nearby joints, highlighting the potential roles of estrogen within and surrounding the IVDs and joints. In addition, estrogen supplementation has been shown to be effective at ameliorating IVD degeneration and OA progression, indicating its potential use as a therapeutic agent for people with LBP and OA pain. This review comprehensively examines the relationship between estrogen and these pain conditions by summarizing recent preclinical and clinical findings. The potential molecular mechanisms by which estrogen may relieve LBP associated with IVD degeneration and FJOA and OA pain are discussed.

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Section: Controversial Results and Risks Associated With Estrogen Tre...mentioning

confidence: 99%

Low back pain and osteoarthritis pain: a perspective of estrogen

et al. 2023

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“…Another limitation of this work is that the mechanistic insights and “treatment” modalities were assessed in silico . Specifically, in silico treatments modeled how a given intervention affected the network, but this approach does not take into account the nuance of timing of treatment initiation,( 14 ) systemic factors, or the downstream impact on tissue morphology and symptom presentation. ( 107 ) While network medicine approaches are robust and have shown great success in identifying molecular insights( 53 ), there is a need to validate these pathway findings and treatments in vivo and in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…( 13 ) Of the few studies that did include females and menopause to study KOA, the predominant menopause model used was ovariectomy (OVX). ( 7, 14 ) However, the fidelity with which OVX recapitulates natural menopause is questionable. Specifically, OVX results in abrupt session of ovarian function, lacks a perimenopausal period (i.e., the gradual transition from regular menstrual cycles to a menopausal state lasting 7-12 years in humans ( 15 )) and disrupts all ovarian sex hormones, including ones that do not normally change in menopause, such as testosterone.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, OVX results in abrupt session of ovarian function, lacks a perimenopausal period (i.e., the gradual transition from regular menstrual cycles to a menopausal state lasting 7-12 years in humans ( 15 )) and disrupts all ovarian sex hormones, including ones that do not normally change in menopause, such as testosterone. ( 7 ) Additionally, OVX studies for KOA have largely employed young animals( 14 ), despite clinical evidence clearly showing that young women who have oophorectomies and older women undergoing natural menopause represent distinct populations with distinct clinical needs. ( 16 ) As such, OVX is unlikely to provide the much-needed biological insights related to natural menopause.…”

Section: Introductionmentioning

confidence: 99%

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

Gilmer

Iijima

Jackson

et al. 2023

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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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