Cytokines, Neuroplasticity Modulators, and Biomarkers in Spinal Canal Stenosis and Endoscopic Decompression

Research Rationale and Study Design Lumbar spinal stenosis (LSS) is a common degenerative musculoskeletal disorder characterized by narrowing of the spinal canal, often leading to pain and disability. One of the primary contributors to this condition is hypertrophy (thickening) of the ligamentum flavum (LF), along with facet joint degeneration, intervertebral disc herniation, and ligament ossification. However, the pathophysiological mechanisms behind these changes remain incompletely understood. Histological changes in hypertrophied LF include fibrocartilaginous metaplasia, type II collagen proliferation, ossification, calcium crystal deposition, and degeneration of elastic and collagen fibers. Both mechanical stress and inflammatory processes, particularly macrophage infiltration, are considered key contributors to degeneration, especially in the aging population. Yet, inflammation linked to systemic metabolic disorders-such as obesity and sarcopenia-may also significantly influence the degeneration of spinal structures. Metabolic Inflammation and the Role of Adipokines Recent research has highlighted the role of adipokines in the pathogenesis of degenerative spinal and joint diseases. Disrupted lipid metabolism and chronic low-grade inflammation contribute to tissue remodeling, extracellular matrix (ECM) degradation, and ectopic fat deposition in spinal structures. Epidural fat, normally present in the spinal canal, can become inflamed and secrete pro-inflammatory cytokines, potentially affecting adjacent tissues such as muscles and ligaments. Conditions like spinal epidural lipomatosis, which is associated with obesity, exemplify this pathological mechanism. While adipokines like leptin and visfatin have been previously associated with LF ossification and degeneration, the presence and role of others-such as adipsin, vaspin, resistin, lipocalin-2, progranulin, chemerin, omentin-1, and GDF-15-have not yet been studied in LF or epidural fat. Given their known effects on inflammation and ECM remodeling, these molecules are strong candidates for involvement in spinal canal narrowing. Research Hypotheses and Objectives This study hypothesizes that adipose tissue-derived cytokines, particularly from epidural fat, contribute to LF degeneration and LSS through inflammatory and metabolic signaling. The main research objectives are to: 1. Identify differences in biomarker concentrations in LF, paraspinal muscle, and epidural fat from patients with and without LSS. 2. Determine correlations between tissue and blood biomarker levels and clinical parameters such as pain, disability, and body mass. 3. Select potential biomarkers for monitoring surgical outcomes of spinal decompression. 4. Identify cytokines that modulate LF inflammation and metabolism. 5. Evaluate the direct effects of adipokines on LF cell behavior in vitro. Study Design and Methods Study population: • 100 patients undergoing lumbar spine surgery at the Orthopaedic-Rehabilitation Clinical Hospital in Poznań: o 50 with LSS (ages 40-90) * 50 with disc herniation only (ages 18-40; control group) Tissue collection (intraoperative): • Ligamentum flavum • Paraspinal muscles • Epidural adipose tissue Blood samples: • Collected from all participants: o Within 48 hours before surgery o Two months post-surgery Clinical assessments: • Disability and pain scales * Preoperative MRI scans Laboratory analysis: • Molecular testing: * mRNA expression of selected cytokines and adipokines using PCR * Protein levels determined via ELISA in both serum and tissue homogenates • Cell culture studies: * One-third of collected tissue is used to establish primary cell cultures from LF, paraspinal muscles, and epidural fat * Cells will be stimulated with conditioned media from epidural fat and with selected recombinant cytokines (e.g., vaspin, lipocalin-2, GDF-15) * Experiments will assess the gene and protein expression of key molecules involved in inflammation, ECM remodeling, bone metabolism, fibrosis, and matrix degradation. The goal is to clarify the local and systemic roles of adipokines and inflammation in the pathogenesis of LF hypertrophy and LSS. This knowledge may aid in identifying biomarkers for disease progression and therapeutic targets for non-surgical interventions in the future.