Department of Developmental Biology, Agharkar Research Institute, Pune, Maharashtra 411004, India.
S P Pune University, Pune, Maharashtra 411007, India.
Development. 2023 Jan 1;150(1). doi: 10.1242/dev.201036. Epub 2023 Jan 6.
Intervertebral disc (IVD) degeneration is the primary cause of back pain in humans. However, the cellular and molecular pathogenesis of IVD degeneration is poorly understood. This study shows that zebrafish IVDs possess distinct and non-overlapping zones of cell proliferation and cell death. We find that, in zebrafish, cellular communication network factor 2a (ccn2a) is expressed in notochord and IVDs. Although IVD development appears normal in ccn2a mutants, the adult mutant IVDs exhibit decreased cell proliferation and increased cell death leading to IVD degeneration. Moreover, Ccn2a overexpression promotes regeneration through accelerating cell proliferation and suppressing cell death in wild-type aged IVDs. Mechanistically, Ccn2a maintains IVD homeostasis and promotes IVD regeneration by enhancing outer annulus fibrosus cell proliferation and suppressing nucleus pulposus cell death through augmenting FGFR1-SHH signaling. These findings reveal that Ccn2a plays a central role in IVD homeostasis and regeneration, which could be exploited for therapeutic intervention in degenerated human discs.
椎间盘（IVD）退变是人类腰痛的主要原因。然而，IVD 退变的细胞和分子发病机制仍不清楚。本研究表明，斑马鱼的 IVD 具有独特且不重叠的细胞增殖和细胞死亡区。我们发现，在斑马鱼中，细胞通讯网络因子 2a（ccn2a）在脊索和 IVD 中表达。尽管 ccn2a 突变体的 IVD 发育似乎正常，但成年突变体的 IVD 表现出细胞增殖减少和细胞死亡增加，导致 IVD 退变。此外，ccn2a 的过表达通过加速细胞增殖和抑制野生型老年 IVD 中的细胞死亡来促进再生。在机制上，ccn2a 通过增强外环纤维环细胞增殖和抑制核髓核细胞死亡，通过增强 FGFR1-SHH 信号传导来维持 IVD 稳态并促进 IVD 再生。这些发现表明，ccn2a 在 IVD 稳态和再生中发挥核心作用，这可能为治疗退变的人类椎间盘提供干预途径。
