Two functions of lysyl oxidase like-2 : extracellular matrix maturation and cell proliferation
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Lysyl oxidase like-2 (LOXL2) was found to be present extracellularly in primary human gingival fibroblast cells. This project has been primarily focused on investigating our hypothesis that LOXL2 may play a critical role in regulating cell proliferation and collagen accumulation in primary human gingival fibroblast cells, which may contribute to the development of fibrotic changes in human gingival tissue. LOXL2 shRNA lentivirus reduced the LOXL2 mRNA and protein expression by 90 – 95%. Knockdown of LOXL2 or inhibition of LOXL2 enzymatic activity strongly inhibited both basal and CCN2/CTGF-stimulated collagen accumulation (p<0.05). Proliferation assays demonstrated a marked decrease in cell proliferation in both the short and long term in LOXL2 shRNA knockdown cells with minimal or no stimulation of cell apoptosis. Pharmacologic inhibition of LOXL2 enzyme activity reduced basal and CCN2/CTGF-stimulated cell proliferation (40% and 50%) in short term cultures. Furthermore, there was 15-20% inhibition seen in long term assays. Recombinant active LOXL2 significantly increased collagen accumulation and cell proliferation (p<0.05). Thereby, our investigation in vitro by loss and gain of function experiments confirmed that LOXL2 is critically required for both gingival fibroblast proliferation and for collagen accumulation in the presence or absence of CCN2/CTGF. LOXL2 stimulation is critical for both proliferation and collagen accumulation in primary human gingival fibroblasts. Lastly, we found that the presence of LOXL2 extracellularly and LOXL2 may regulate cell proliferation by enhancing the phosphorylation of PDGFR.