Abstract
The intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.
Highlights
Low back pain (LBP) is a debilitating condition that affects ~84% of the population in their lifetime.[1]
An in vitro study suggested a surgery compared with controls (Supplementary Fig. 2C-F). These possible association of HIF1α with Disc degeneration disease (DDD) pathogenesis,[20] the findings indicate that HIF1α expression in EP and annulus fibrosus (AF) tissues is in vivo functions of Hypoxia-inducible factors (HIFs) in regulating intervertebral disc (IVD) homeostasis and/or spatiotemporally regulated during DDD pathogenesis, implying a DDD pathogenesis remain elusive
In this study, utilizing human degenerative IVD tissues and deletion of Vhl in Col2a1-positive cells in adult mice mouse models of DDD, we found that among the HIF family To further explore the role of HIF signaling in IVD maintenance members, Hif1α expression was significantly upregulated in EP and AF tissues of degenerated discs
Summary
Low back pain (LBP) is a debilitating condition that affects ~84% of the population in their lifetime.[1] LBP affects physical function, reduces quality of life, and causes psychological distress.[2] LBP is a multifactorial disease, studies report that intervertebral disc (IVD) degeneration is the main contributing factor. IVD degeneration is a common musculoskeletal disorder caused by multiple factors, such as aging, altered metabolism and genetic predisposition.[3,4,5] Current therapies for IVD degeneration mainly include pain relief through physical rehabilitation therapy or surgical treatment. A few effective disease-modifying treatments are available for IVD degeneration, as its pathogenic mechanism is not fully known.[6,7,8] Understanding the molecular mechanisms of IVD degeneration is important for the development of novel biotherapeutics
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