Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Abstract

Background/Aims: Hypertrophic ligamentum flavum (LF) is a major cause of lumbar spinal stenosis. Our previous work showed that high levels of lysophosphatidic acid (LPA) expression are positively correlated with LF hypertrophy. This study aimed to further unveil how LPA regulates LF hypertrophy Methods: We studied LPAR1 expression in human LF cells using PCR and western blotting. Cell viability cell cycle, apoptosis rate and molecular mechanisms were assayed in LPAR1 knockdown or overexpression LF cells. LF hypertrophy and the molecular mechanism was confirmed in human samples and in in vivo studies. Results: The expression of LPA and its receptor LPAR1 is significantly higher in tissues or cells harvested from hypertrophic LF compared to healthy controls. Moreover, LPA promoted LF cell proliferation by interacting with LPAR1. This conclusion is supported by the fact that depletion or overexpression of LPAR1 changed the effect of LPA on LF cell proliferation. LPA also inhibits apoptosis in LF cells through the receptor LPAR1. Importantly, we demonstrated that the LPA-LPAR1 interaction initiated Akt phosphorylation and determined cell proliferation and apoptosis. Our in vitro findings were supported by our in vivo evidence that lyophilized LPA significantly induced LF hypertrophy via the LPAR1-Akt signaling pathway. More importantly, targeted inhibition of LPAR1 by Ki16425 with a gel sponge implant effectively reduced LPA-associated LF hypertrophy. Taken together, these data indicate that LPA binds to the receptor LPAR1 to induce LF cell proliferation and inhibit apoptosis by activating AKT signaling cascades. Targeting this signaling cascade with Ki16425 is a potential therapeutic strategy for preventing LF hypertrophy. Conclusion: LPA-LPAR1-Akt activation is positively correlated with the proliferation and survival of LF cells. LPAR1 could be a target for new drugs and the development of new therapeutic methods for treating LF hypertrophy.

Ligamentum flavum fibrosis and hypertrophy: Molecular pathways, cellular mechanisms, and future directions

“…Targeting this signaling cascade with inhibitor (Ki16425) can reduce this response, thereby suggesting a potential therapeutic strategy for preventing LF fibrosis. 176…”

Development of an In Vitro 3D Model for Investigating Ligamentum Flavum Hypertrophy

“…Recent work has revealed enhanced cell proliferation and pronounced cell cluster formation in LFH tissue compared with non-LFH tissue [15]. These clusters may play a key role in the progression and pathogenesis of LFH.…”

Hypertrophy of the Ligamentum Flavum in Lumbar Spinal Canal Stenosis is Associated with Abnormal Accumulation of Specific Lipids

“…Zhou et al described that LPA concentration in the cerebrospinal uid of patients with HLF was higher than those in subjects with NHLF, and LPA induced hypertrophy of LF via LPA receptor1 to Akt signal pathway. 22 However, their study did not show the lipid distributions in HLF. In that respect, our study shows the importance of evaluating the lipids pro les of HLF.…”