Meta-analysis Integrated With Multi-omics Data Analysis to Elucidate Pathogenic Mechanisms of Age-Related Knee Osteoarthritis in Mice

Iijima, Hirotaka; Gilmer, Gabrielle; Wang, Kai; Sivakumar, Sruthi; Evans, Christopher H.; Matsui, Yusuke; Ambrosio, Fabrisia

doi:10.1093/gerona/glab386

Cited by 12 publications

(10 citation statements)

References 101 publications

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“…1F ) 18 . A recent systematic review identified elevated inflammation, increased senescence, and impaired autophagy as common denominators associated with aging-induced KOA in mice 19 , all of which are downstream of α-Klotho 20 – 24 . When we accessed archived microarray data (GSE80285) 25 , we found that inhibition of α-Klotho protein significantly activated PI3K/Akt signaling in human primary chondrocytes in vitro (Fig.…”

Section: Resultsmentioning

confidence: 99%

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

et al. 2023

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Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.

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Section: Resultsmentioning

confidence: 99%

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

et al. 2023

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“…Of the 24 preclinical studies listed in Table 1, 20 were performed in animal models that required surgical destabilization of the joint. While these models are likely to be relevant to posttraumatic OA, their relevance to idiopathic OA, the majority manifestation, is unclear [21]. Likewise, two of the listed studies used MIA, an inhibitor of glycolysis, to induce OA.…”

Section: Preclinical Evaluation In Animal Models Of Osteoarthritismentioning

confidence: 99%

Osteoarthritis gene therapy in 2022

Evans

Ghivizzani

Robbins

2022

Current Opinion in Rheumatology

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Purpose of reviewTo assess the present status of gene therapy for osteoarthritis (OA). Recent findingsAn expanding list of cDNAs show therapeutic activity when introduced into the joints of animals with experimental models of OA. In vivo delivery with adenovirus or adeno-associated virus is most commonly used for this purpose. The list of encoded products includes cytokines, cytokine antagonists, enzymes, enzyme inhibitors, growth factors and noncoding RNA. Elements of CRISPR-Cas have also been delivered to mouse knees to ablate key genes. Several human trials have been initiated, using transgenes encoding transforming growth factor-b 1 , interleukin-1 receptor antagonist, interferon-b, the NKX3.2 transcription factor or variant interleukin-10. The first of these, using ex vivo delivery with allogeneic chondrocytes, gained approval in Korea which was subsequently retracted. However, it is undergoing Phase III clinical trials in the United States. The other trials are in Phase I or II. No gene therapy for OA has current marketing approval in any jurisdiction.

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“…( 10 ) Although KOA is twice as likely to present in post-menopausal women than in men ( 11, 12 ), a recent systematic review showed that approximately 75% of murine studies of KOA only included males. ( 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.…”

Section: Introductionmentioning

confidence: 99%

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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Meta-analysis Integrated With Multi-omics Data Analysis to Elucidate Pathogenic Mechanisms of Age-Related Knee Osteoarthritis in Mice

Cited by 12 publications

References 101 publications

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

Osteoarthritis gene therapy in 2022

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

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