Berberine Modulates LPA Function to Inhibit the Proliferation and Inflammation of FLS-RA via p38ERK MAPK Pathway Mediated by LPA1

الملخص EN

Objective.

This study aimed to investigate whether berberine exerted anti-inflammatory and antiproliferative effects on the fibroblast-like synoviocytes of rheumatoid arthritis (FLS-RA) through regulating the lysophosphatidic acid (LPA) function.

Methods.

Firstly, the expression levels of LPA and lysophosphatidic acid receptor 1 (LPA1) in RA patients, osteoarthritis (OA) patients, and healthy controls were detected.

Moreover, molecular docking was employed to characterize the binding sites of berberine in the predicted protein targets.

Later, FLS-RA were stimulated using berberine, LPA, and the specific inhibitor (Ki16425) of LPA1, thereafter, the effects on the proliferation, apoptosis, the release of inflammatory mediators of FLS-RA, and the MAPK pathway were observed.

Results.

Compared with healthy controls (n = 25), the plasma LPA level (n = 28) and synovial fluid (n = 10) were markedly higher in RA patients.

LPA1 was highly expressed in RA patients (n = 4) relative to that in OA patients (n = 4).

Berberine remarkably inhibited the proliferation and the excessive production of IL-6 and TNF-α in FLS-RA, whereas suppressing the expression of K-ras, c-Raf, and p-38/ERK-phosphorylation.

In addition, berberine inhibited the LPA-induced p-38/ERK-phosphorylation through binding to LPA1.

Conclusions.

LPA plays a certain role in promoting the proliferation and inflammation of FLS-RA.

Berberine potentially modulates LPA function to suppress the proliferation and inflammation of FLS-RA through blocking the p38/ERK MAPK pathway mediated by LPA1.

These findings suggest that, berberine possesses potential lipid-regulating, antiarthritis, and synovial hyperplasia inhibition activities against RA, which may provide a promising therapeutic target for the clinical drug development for RA patients with dyslipidemia and high CVD risk.