Abstract
Lumbar intervertebral disc degeneration (IVDD) is the most common cause of low back pain (LBP). Among all the factors leading to IVDD, lumbar cartilage endplate (LCE) degeneration is considered a key factor. In the present study, we investigate the effect and regulation of carbonic anhydrase 12 (CA12) in LCE, which catalyzes hydration of CO2 and participates in a variety of biological processes, including acid–base balance and calcification. Our results show that CA12, downregulated in degenerated LCE, could maintain anabolism and prevent calcification in the endplate. Furthermore, CA12 is regulated by the IGF-1/IGF-1R/PI3K/CREB signaling pathway. When we overexpressed CA12 in LCE, the decreased anabolism induced by inflammatory cytokine could be rescued. In contrast, reducing CA12 expression, either with siRNA, PI3Kinhibitor, or CREB inhibitor, could downregulate anabolism and cause apoptosis and then calcification in LCE. The protective effects of IGF-1 are even diminished with low-expressed CA12. Similar results are also obtained in an ex vivo model. Consequently, our results reveal a novel pathway, IGF-1/IGF-1R/PI3K/CREB/CA12, that takes a protective role in LCE degeneration by maintaining anabolism and preventing calcification and apoptosis. This study proposes a novel molecular target, CA12, to delay LCE degeneration.
Highlights
Low back pain disturbs people of all ages and contributes to a large share of disease burden and disability globally (Driscoll et al, 2014; Maher et al, 2017)
Combined with our previous data revealing an interaction between carbonic anhydrase 12 (CA12) downregulation and nucleus pulposus (Chen et al, 2016), we assumed that CA12 and endplate cartilage (EPC) degeneration were highly associated as well
Apart from the role of CA12 in EPC degeneration, the specific pathway regulating CA12 in EPC degeneration remains elusive. With those questions in mind, our study finds that CA12 could protect the endplate and is regulated by the Insulin-like growth factor 1 (IGF-1)/PI3K/RAC/MSK1/CREB signaling pathway
Summary
Low back pain disturbs people of all ages and contributes to a large share of disease burden and disability globally (Driscoll et al, 2014; Maher et al, 2017). Among all the factors resulting in IVDD, endplate cartilage degeneration is considered a leading cause (Adams and Roughley, 2006). A Research of Endplate Cartilage with low back pain (Jensen et al, 2008) and IVDD (Adams and Roughley, 2006). This is corroborated by previous studies revealing that endplate degeneration could lead to IVDD in animal models (Holm et al, 2004). Researchers find endplate calcification responsible for IVDD by decreasing the permeability of the endplate (Rodriguez et al, 2011). For both researchers and surgeons, endplate degeneration presents a rational and promising target for IVDD
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