Genetic and pharmacologic suppression of PPARγ enhances NELL-1-stimulated bone regeneration

Recent investigations into mechanisms behind the development of osteoporosis suggest that suppressing PPAR gamma-mediated adipogenesis can improve bone formation and bone mineral density. In this study, we investigated a co -treatment strategy to enhance bone formation by combining NELL-1, an osteogenic molecule that has been extensively studied for its potential use as a therapeutic for osteoporosis, with two methods of PPAR gamma sup-pression. First, we suppressed PPAR gamma genetically using lentiviral PPAR gamma-shRNA in immunocompromised mice for a proof of concept. Second, we used a PPAR gamma antagonist to suppress PPAR gamma pharmacologically in immuno-competent senile osteopenic mice for clinical transability. We found that the co-treatment strategy significantly increased bone formation, increased the proliferation stage cell population, decreased late apoptosis of primary mouse BMSCs, and increased osteogenic marker mRNA levels in comparison to the single agent treatment groups. The addition of PPAR gamma suppression to NELL-1 therapy enhanced NELL-1's effects on bone formation by upregulating anabolic processes without altering NELL-1's inhibitory effects on osteoclastic and adipogenic activities. Our findings suggest that combining PPAR gamma suppression with therapeutic NELL-1 may be a viable method that can be further developed as a novel strategy to reverse bone loss and decrease marrow adiposity in age-related osteoporosis.

Automated summary

Recent investigations have shown that suppressing PPAR gamma-mediated adipogenesis can improve bone formation in osteoporosis. This study explores a co-treatment strategy using NELL-1 and PPAR gamma suppression, which significantly enhanced bone formation and increased cell proliferation while decreasing apoptosis in mice. This suggests that combining PPAR gamma suppression with NELL-1 therapy may be a promising method to reverse bone loss in osteoporosis.