Abstract
BackgroundIntervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis.MethodsRecombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed.ResultsRecombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex.ConclusionsThe current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.
Highlights
Low back pain (LBP) is one of the most common and expensive health problems, affecting about 80% of the population during their life with total costs exceeding $100 billion per year [1, 2]
TNF-α increases Notch ligand expression in nucleus pulposus (NP) cells The results showed that TNF-α treatment increased the expression of JAG2 mRNA (Fig. 1a) and protein (Fig. 1c, d), whereas there was little change in the expression of JAG1 and Dll4 (Fig. 1a, b); the expression of Dll1 was suppressed by TNF-α (Fig. 1b)
The results indicated a significant increase in the expression of Hes1 (2.2-fold), Hes5 (1.1-fold), Hey1 (1.3-fold), and Hey2 (1.9-fold), demonstrating the activation of Notch signaling in response to JAG2 treatment (Fig. 1f, g)
Summary
Low back pain (LBP) is one of the most common and expensive health problems, affecting about 80% of the population during their life with total costs exceeding $100 billion per year [1, 2]. Intervertebral disc degeneration (IVDD)-related disorders are the major causes of LBP and associated disability [3]. Many studies have found that cytokines mediate the shift in NP cell function and promote abnormal proliferation and apoptosis [9, 10]. Various factors, including aging, genetics, nutrition, metabolic factors, infection, mechanical factors, signaling networks, and inflammatory cytokines, induce NP cell apoptosis, which results in progressive IVDD [12, 13]. Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. We aimed to investigate the role of JAG2/Notch in NP cell proliferation and apoptosis
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