SMBD-Jewish General Hospital, Lady Davis Institute for Medical Research, Montreal, QC, Canada.
Eur Cell Mater. 2013 May 2;25:268-83. doi: 10.22203/ecm.v025a19.
In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca(2+), inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (200 %) and NP cells (163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca(2+) release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs.
在退行性椎间盘（IVD）中，已证明存在 X 型胶原（COL X）的表达（与肥大分化相关）和钙化。在椎间盘退变过程中抑制 COL X 的表达和钙化可能具有治疗作用。在本研究中，我们研究了人甲状旁腺激素 1-34（PTH）抑制钙化潜力指标（碱性磷酸酶（ALP）、Ca(2+)、无机磷酸盐（Pi））和 COL X 表达的潜力。此外，我们试图阐明 PTH 在人腰椎 IVD 中具有中度至晚期退变的纤维环（AF）和髓核（NP）细胞中的作用机制。分析了有丝分裂原激活的蛋白激酶（MAPK）信号转导和钙化潜力标志物的变化。PTH 增加了 AF（200%）和 NP 细胞（163%）中 COL II 的表达，并降低了 AF 和 NP 细胞中 COL X 的水平（~75%）。COL 基因表达的这些变化先于 MAPK 磷酸化，PTH 在 30 分钟后增加了 AF 和 NP 细胞中的 MAPK 磷酸化。MAPK 信号转导抑制剂 U0126 和蛋白激酶 A 抑制剂 H-89 DCH 减弱了 PTH 对两种细胞类型中 COL II 表达的刺激作用。PTH 仅在 NP 细胞中降低了 ALP 活性并增加了 Ca(2+)释放。本研究表明，PTH 可能通过 MAPK 和 PKA 信号通路刺激基质合成并抑制退变椎间盘细胞中的钙化潜力标志物，从而潜在地延缓 IVD 退变。因此，抑制进一步的矿化沉积可能是改善退变椎间盘状态的可行治疗选择。
