Dataset Information

Focusing on the hypoxia-inducible factor pathway: role, regulation, and therapy for osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is a common chronic disabling disease that affects hundreds of millions of people around the world. The most important pathological feature is the rupture and loss of articular cartilage, and the characteristics of avascular joint tissues lead to limited repair ability. Currently, there is no effective treatment to prevent cartilage degeneration. Studies on the mechanism of cartilage metabolism revealed that hypoxia-inducible factors (HIFs) are key regulatory genes that maintain the balance of cartilage catabolism-matrix anabolism and are considered to be the major OA regulator and promising OA treatment target. Although the exact mechanism of HIFs in OA needs to be further clarified, many drugs that directly or indirectly act on HIF signaling pathways have been confirmed by animal experiments and regarded as promising treatments for OA. Targeting HIFs will provide a promising strategy for the development of new OA drugs. This article reviews the regulation of HIFs on intra-articular cartilage homeostasis and its influence on the progression of osteoarthritis and summarizes the recent advances in OA therapies targeting the HIF system.

SUBMITTER: Guo H

PROVIDER: S-EPMC9743529 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Focusing on the hypoxia-inducible factor pathway: role, regulation, and therapy for osteoarthritis.

Guo Hanhan H Huang Jianghong J Liang Yujie Y Wang Daping D Zhang Huawei H

European journal of medical research 20221212 1

Osteoarthritis (OA) is a common chronic disabling disease that affects hundreds of millions of people around the world. The most important pathological feature is the rupture and loss of articular cartilage, and the characteristics of avascular joint tissues lead to limited repair ability. Currently, there is no effective treatment to prevent cartilage degeneration. Studies on the mechanism of cartilage metabolism revealed that hypoxia-inducible factors (HIFs) are key regulatory genes that maint ...[more]

PMID: 36503684

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Project description:Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2.In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ER?, HER2, and HIF-1? (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ER? to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1? to determine its importance.Basal HIF-1? protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF-1? expression in AI-resistant cells is likely regulated by HER2 activated-phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1? affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP.One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target.

Dataset Information

Focusing on the hypoxia-inducible factor pathway: role, regulation, and therapy for osteoarthritis.

Publications

Focusing on the hypoxia-inducible factor pathway: role, regulation, and therapy for osteoarthritis.

Similar Datasets

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