The Role of Cytokines and Neuroplasticity Modulators in the Development of Spinal Canal Stenosis and the Identification of Biomarkers for the Biochemical Evaluation of Treatment in Patients Undergoing Endoscopic Spinal Canal Decompression

Spinal stenosis is a common musculoskeletal disorder that causes pain or disability in patients. However, the pathogenesis of this disease is complex and has not yet been fully elucidated. Lumbar spinal canal stenosis results from degenerative changes in structures located behind the spinal cord, such as hypertrophy of the ligamentum flavum (LF), as well as ligament calcification, degeneration and hypertrophy of the facet joints and/or herniation of intervertebral discs located anterior to the spinal cord. The pathology of LF hypertrophy includes fibrocartilaginous changes associated with type II collagen proliferation, ossification, calcium crystal deposition, degeneration of collagen and elastic fibers, and chondroid metaplasia of ligament fibroblasts. Numerous scientific studies have attempted to explore the etiology of hypertrophy and ossification of spinal ligaments, considering systemic, local, genetic, and environmental factors. However, the mechanism of degeneration development is still not fully understood. Besides mechanical stress and increased collagen synthesis (fibrosis) in the ligament, which make age a major risk factor, the presence of inflammation and macrophage infiltration is considered a significant contributor to degeneration development.

Therefore, it is reasonable to assume that the presence of inflammation associated with other health conditions-especially chronic ones-may, to an unknown extent, influence the course of spinal structure degeneration. Currently, obesity and sarcopenia are drawing particular attention as disorders affecting all systems of the human body. Since their prevalence is increasing, a thorough understanding of their consequences on individual organs has significant social and practical importance for prevention and health protection.

An increasing number of reports indicate that disturbances in lipid metabolism and the secretion of pro-inflammatory adipokines and cytokines are deeply involved in regulating cellular phenotypes and fates, extracellular matrix metabolism, and inflammation in the pathophysiological processes of degenerative spinal and joint diseases. Metabolic disorders can affect bone metabolism and lead to ectopic ossification and fat deposition not only in spinal ligaments but also in other spinal structures. Also noteworthy is the influence of the adipokinome on the development of musculoskeletal degenerative disorders. Even anatomically present epidural fat in the spinal canal may become inflamed and spontaneously secrete inflammatory cytokines, potentially modifying the function of adjacent tissues, such as paraspinal muscles and ligaments. It is worth mentioning that spinal epidural lipomatosis, characterized by an excess of fat tissue in the epidural space leading to spinal canal stenosis, is strongly associated with obesity.

So far, it has been confirmed that adipokines and their receptors, although primarily located in white adipose tissue, are also present in joint cartilage and spinal bone marrow. Adipokines may promote ligamentum flavum degeneration by stimulating inflammatory responses and promoting pathological changes. Leptin has been shown to significantly correlate with the number of vertebrae affected by ligamentous ossification. Fan et al. discovered that leptin markedly upregulates alkaline phosphatase and osteocalcin mRNA expression in ligamentum flavum cells. High levels of visfatin have also been found in the ligamenta flava of patients with confirmed ossification. There is no available data on the presence and role of other adipose tissue-derived cytokines such as adipsin, vaspin, resistin, lipocalin-2, progranulin, chemerin, omentin-1, or growth differentiation factor-15 (GDF-15) in the ligamentum flavum. It is highly likely that these cytokines are also involved in the development of spinal canal stenosis, which constitutes our research hypothesis. The presence and levels of these cytokines in epidural fat tissue in patients with stenosis, compared to those without spinal canal narrowing, have not been studied to date. Since studies confirm that chronic systemic inflammation affects various tissues and local inflammation significantly affects neighboring structures, we hypothesize that ligaments, paraspinal muscles, intervertebral discs, etc., may be particularly vulnerable to cytokines secreted by epidural fat tissue. Previous in vitro studies confirmed that a local environment rich in cytokines such as IL-6, IL-1α, nitric oxide donor (SNAP), and prostaglandin E2 changes the gene expression of collagens I, V, XI, and osteocalcin in ligamentum flavum cells. However, the impact of the mentioned adipokines on the development of ligamentum flavum degeneration has not yet been determined.

The study will involve examining the concentrations of cytokines (especially adipokines) and neuroplasticity modulators and their mRNA expression in tissues routinely removed from patients with spinal stenosis and disc herniation during surgery, as well as collecting blood from patients twice, before the procedure and during a follow-up visit two months after the procedure.