AUTOCRINE AND PARACRINE OF HOMEOSTASIS OF THE INTERVERTEBRAL DISC

我们已经记录了胶原蛋白代谢中与年龄相关和退化相关的变化， 蛋白聚糖和人类椎间盘中的基质降解酶。我们的研究 (i) 证实了 细胞因子和生长因子在椎间盘退变和修复中发挥关键作用，(ii) 证明某些生长因子抑制细胞因子的自分泌产生，并且细胞因子 抑制剂可以改变基质分子和金属蛋白酶合成的基础水平，并且（iii）发现 在椎间盘晚期阶段，双糖链蛋白聚糖的表达量高于其他小蛋白聚糖 退化和老供体椎间盘的退化，并在基质稳态中发挥重要的调节作用。 我们的数据表明，生长因子、细胞因子和调节分子之间的复杂平衡非常重要 用于维持组织稳态。我们建议在未来五年内调查 生长因子、细胞因子和各种调节分子之间的作用机制和相互作用 为了确定它们各自在组织稳态中的作用及其在促进组织中的潜在用途 修复。假设1：生长因子对椎间盘的影响受其产生的调节 椎间盘细胞和抑制因子的存在产生细胞因子；生长因子具有 这些细胞因子的产生产生负反馈。假设2：调控机制 细胞因子和生长因子的基质稳态在椎间盘退变的不同阶段有所不同，因为 椎间盘内原位细胞微环境的变化。对细胞因子和生长的反应 因素以及基质降解酶的产生和激活在后期会有所不同 椎间盘退变。假设3：细胞因子阻断剂对细胞因子作用的抑制及其抑制作用 生长因子产生的细胞因子可以延缓或逆转椎间盘的退变状态 椎间盘早期和中期可观察到的细胞微环境中的细胞 退化。腰痛造成巨大的人类痛苦、高昂的医疗费用和 造成重大社会经济损失。尽管背痛的病因通常未知，但椎间孔 椎间盘突出是背部问题的重要根源。这项研究的结果将推动生物领域的发展 椎间盘退变的治疗和组织工程。

We have documented age-related and degeneration-related changes in the metabolism of collagens, proteoglycans, and matrix-degrading enzymes in the human intervertebral disc. Our studies (i) confirmed the pivotal roles that cytokines and growth factors play in intervertebral disc degeneration and repair, (ii) demonstrated that certain growth factors inhibit the autocrine production of cytokines and that cytokine inhibitors can change basal levels of synthesis of matrix molecules and metalloproteinases, and (iii) found that biglycan was expressed in greater amounts than other small proteoglycans during late stages of disc degeneration and in the discs of old donors and plays an important regulatory role in matrix homeostasis. Our data suggest that an intricate balance of growth factors, cytokines and regulatory molecules is important for the maintenance of tissue homeostasis. Over the next five years, we propose to investigate the mechanisms of action and the interplay between growth factors, cytokines and various regulatory molecules in order to determine their respective roles in tissue homeostasis and their potential use in promoting tissue repair. Hypothesis 1: The effects of growth factors on the intervertebral disc are regulated by the production of cytokines by intervertebral disc cells and by the presence of inhibitory factors; growth factors have a negative feed back on the production of these cytokines. Hypothesis 2: The regulatory mechanisms of matrix homeostasis by cytokines and growth factors vary at different stages of disc degeneration because of changes in the cellular microenvironment in situ within the disc. The response to cytokines and growth factors and the production and activation of matrix-degrading enzymes will be different at advanced stages of disc degeneration. Hypothesis 3: The inhibition of cytokine action by cytokine blockers and the inhibition of cytokine production by growth factors can delay or reverse the degenerative status of intervertebral disc cells in the cellular microenvironment that can be observed in the early and middle stages of disc degeneration. Low back pain is responsible for enormous human suffering, high health care costs and significant socioeconomic losses. Although the etiology of back pain is often unknown, the intervertebral disc is a significant source of back problems. The results from this study will advance the field of biological treatment and tissue engineering for intervertebral disc degeneration.