gms | German Medical Science

Objective: Ligamentum flavum hypertrophy (LFH) is a major contributor in lumbar spinal canal stenosis (LSCS) but its pathophysiology is seldom known. The following static one-way algorithm was suggested as a mechanism of LFH; mechanical stress, inflammation, angiogenesis, and fibrosis occurring in consecutive order. Most of the studies explained the mechanism in two groups, LSCS and non-LSCS, regarding the thickened LF is fixed in discrete category. However, a number of results show mismatch among the studies so the explanations are often paradoxical. We proposed three hypothesis. The LFH is a dynamic and complex mechanism that all the steps are blended so the growth factors/cytokines which contribute for hypertrophy would have common tendency according to the “hypertrophic activity”. Secondly, this hypertrophic activity would correlate with collagen synthesis, not the thickness of LF. Third, LF tissue in high hypertrophic activity would contain active form of fibroblast, so called myofibroblast.

Method: We studied 60 LF samples of patients who underwent lumbar surgery. The mRNA and protein level of angiopoietin-2, TGF-beta, FGF-1, TRPM7, VEGF, Elastin, Collagen-1, 3, 4, 5, and 11 were investigated with real time RT-PCR and representative samples which showed high or low hypertrophic activities were grouped and validated with western blotting. Immunohistochemistry study was used to figure out myofibroblast, staining with a-SMA. Clinical and radiologic data, including the thickness of LF, were considered either.

Results: Angiopoietin-2, TGF-beta, FGF-1, TRPM7 (an ion channels/kinase which is novel substance in this field) and VEGF showed positive correlation with each other (p<0.05). This represents the various steps of hypertrophy mechanism occur simultaneously. All these factors also correlate positively with collagen-1, 3, and 11 which are final product of LFH (p<0.05). This explains the above factors are related with the hypertrophy mechanism and collagen 1, 3, and 11 are likely to be the final products. Angiopoietin-2 (r=0.358, p=0.013) and TGF-beta (r=0.720, p<0.001) also showed positive correlation with elastin either which propose that although the proportion of elastin/collagen decrease, the absolute sum of elastin could be increased. VEGF was the only factor which showed correlation with thickness of LF (p=0.14). Beside the effect of angiogenesis as a link between inflammation and fibrosis, we estimated the angiogenic factor could be induced by hypoxia due to mass growth. Myofibroblast do exist in LF and the active hypertrophic LF cells showed high myofibroblast/fibroblast proportion.

Conclusions: The mechanism of LFH has various steps blended with common tendency and the hypertrophic activity could be explained with collagen synthesis. Myofibroblast is derived from fibroblast like LF cell and this might have key function in LFH mechanism.