The Function And Mechanism Of LPA-LPAR1 And DDRGK1 In The Regulation Of Lumbar Spinal Stenosis

Objective:(1)Correlation analyze lysophosphatidic acid(LPA)and its receptor(LPAR1)expression with ligamentum flavum hypertrophy;(2)Conceal the mechanism of LPA-LPAR1 in the regulation of ligamentum flavum hypertrophy;(3)Correlation analyze of DDRGK1 expression with nucleus pulposus degeneration;(4)Explore the mechanism of DDRGK1 in the regulation of nucleus pulposus degeneration;(5)Provide a new direction of clinical diagnosis and treatment for lumbar spinal stenosis caused by intervertebral disc degeneration and ligamentum flavum hypertrophy.Methods:(1)Correlation analyze LPAR1 expression of human ligamentum flavum cells with the thickness of ligamentum flavum;(2)Detect cell viability,cell cycle,cell apoptosis rate and the cell molecular mechanism in LPAR1 silencing or overexpression of ligamentum flavum cells;(3)Confirm that LPA can promote ligamentum flavum hypertrophy and its molecular mechanism in human specimens and in vivo studies;(4)Conceal the DDRGK1 expression level in the different degeneration stages of nucleus pulposus cells;(5)Study the cell cycle,extracellular matrix synthesis and metabolism and cell molecular mechanism in DDRGK1 silencing or overexpression of nucleus pulposus cells.Results:(1)The expression of LPA and LPAR1 in the tissue and cells from hypertrophic ligamentum flavum group is significantly higher than that in nonhypertrophic ligamentum flavum group;(2)LPA-LPAR1 launches Akt phosphorylation to promote proliferation and anti-apoptosis of ligamentum flavum cells.LPAR1 silencing and overexpression can altered the activation of LPA-LPAR1-Akt signaling axis to influence ligamentum flavum cells proliferation and apoptosis;(3)the freeze-dried LPA induces the hypertrophy of ligamentum flavum through LPAR1-Akt signaling pathway,and targeted LPAR1 inhibition drugs(Ki16425)can effectively reduce LPA induced hypertrophy of ligamentum flavum;(4)The expression of DDRGK1 deceases with the degeneration of nucleus pulposus;(5)DDRGK1 promotes nucleus pulposus cell proliferation and inhibition of extracellular matrix degradation.Conclusion: Activation of LPA-LPAR1-Akt is an important reason for increasing the proliferation and anti-apoptosis of ligamentum flavum and leading to lumbar spinal stenosis,while the low expression of DDRGK1 promotes degeneration of the nucleus pulposus and causes lumbar spinal stenosis.Both LPAR1 and DDRGK1 can be the target of new drugs and new treatment methods for lumbar spinal stenosis.