Carbonic Anhydrase 12 Protects Endplate Cartilage From Degeneration Regulated by IGF-1/PI3K/CREB Signaling Pathway

Xing Zhao; Panyang Shen; Haidong Li; Yute Yang; Jiandong Guo; Shuai Chen; Yan Ma; Jiamin Sheng; Shuying Shen; Gang Liu; Xiangqian Fang

doi:10.3389/fcell.2020.595969

Carbonic Anhydrase 12 Protects Endplate Cartilage From Degeneration Regulated by IGF-1/PI3K/CREB Signaling Pathway

Front Cell Dev Biol. 2020 Oct 16:8:595969. doi: 10.3389/fcell.2020.595969. eCollection 2020.

Authors

Xing Zhao^{1

2}, Panyang Shen^{1

2}, Haidong Li^{1

2

3}, Yute Yang^{1

2}, Jiandong Guo^{1

2}, Shuai Chen^{1

2}, Yan Ma^{1

2}, Jiamin Sheng⁴, Shuying Shen^{1

2}, Gang Liu^{1

2}, Xiangqian Fang^{1

2}

Affiliations

¹ Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
³ Department of Spine Surgery, First People's Hospital Affiliated to the Huzhou University Medical College, Huzhou, China.
⁴ The Second Clinical College, Wenzhou Medical University, Wenzhou, China.

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.

Keywords: IGF-1; carbonic anhydrase 12; degeneration; endplate cartilage; low back pain.