Ferguson Laboratory for Spine Research, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
Biomolecules. 2024 Oct 10;14(10):1277. doi: 10.3390/biom14101277.
Hypertrophy of the ligamentum flavum (HLF) is a common contributor to lumbar spinal stenosis (LSS). Fibrosis is a core pathological factor of HLF resulting in degenerative LSS and associated low back pain. Although progress has been made in HLF research, the specific molecular mechanisms that promote HLF remain to be defined. The molecular factors involved in the onset of HLF include increases in inflammatory cytokines such as transforming growth factor (TGF)-β, matrix metalloproteinases, and pro-fibrotic growth factors. In this review, we discuss the current understanding of the mechanisms involved in HLF with a particular emphasis on aging and mechanical stress. We also discuss in detail how several pathomechanisms such as fibrosis, proliferation and apoptosis, macrophage infiltration, and autophagy, in addition to several molecular pathways involving TGF-β1, mitogen-activated protein kinase (MAPKs), and nuclear factor-κB (NF-κB) signaling, PI3K/AKT signaling, Wnt signaling, micro-RNAs, extracellular matrix proteins, reactive oxygen species (ROS), etc. are involved in fibrosis leading to HLF. We also present a summary of the current advancements in preclinical animal models for HLF research. In addition, we update the current and potential therapeutic targets/agents against HLF. An improved understanding of the molecular processes behind HLF and a novel animal model are key to developing effective LSS prevention and treatment strategies.
黄韧带肥厚（HLF）是腰椎管狭窄症（LSS）的常见病因。纤维化是 HLF 的核心病理因素，导致退行性 LSS 和相关的下腰痛。尽管 HLF 研究取得了进展，但促进 HLF 的具体分子机制仍有待确定。HLF 发病涉及的分子因素包括转化生长因子（TGF）-β、基质金属蛋白酶和促纤维化生长因子等炎症细胞因子的增加。在这篇综述中，我们讨论了目前对 HLF 相关机制的理解，特别强调了衰老和机械应激的作用。我们还详细讨论了纤维化、增殖和凋亡、巨噬细胞浸润和自噬等几种病理机制，以及涉及 TGF-β1、丝裂原活化蛋白激酶（MAPKs）和核因子-κB（NF-κB）信号、PI3K/AKT 信号、Wnt 信号、微小 RNA、细胞外基质蛋白、活性氧（ROS）等多种分子途径如何参与导致 HLF 的纤维化。我们还总结了目前用于 HLF 研究的临床前动物模型的进展。此外，我们更新了针对 HLF 的当前和潜在治疗靶点/药物。深入了解 HLF 背后的分子过程和新型动物模型是开发有效 LSS 预防和治疗策略的关键。
