UCLA

Osteoporosis is a metabolic bone disease where decreased bone quality and quantity increases the rate of fractures. It serves as one of the largest skeletal aging problems worldwide. Like many other chronic diseases, osteoporosis affects the majority of the elderly population, especially females after menopause. The prevalence of bone disease and fractures is projected to increase markedly as the population increases(1). Bone disease and many other factors related to fractures will have an enormous impact on the future well-being of Americans and worldwide.

NELL-1 is an osteogenic, secretory molecule previously shown to enhance bone regeneration in various rodent and ovine skeletal defect models. Systemic delivery of NELL-1 via intravenous (IV) injections not only increases murine bone mineral density (BMD) and percent bone volume, but also increases new bone formation throughout the overall skeleton(2). Astoundingly, in the past, we have shown that systemic delivery of NELL-1 induces robust bone formation in healthy mice, which were injected intravenously every 7 days. Here, we investigate the potential of systemic administration of PEGylated NELL-1 (NELL-PEG) every 7 days to see the increases in femoral BMD, percent bone volume and also new bone formation throughout the overall skeleton after four weeks of treatment to reverse ovariectomy (OVX)-induced osteoporotic bone loss in mice. First, we have successfully established osteoporotic mouse model that mimics the human post-menopausal osteoporosis by surgical removal of ovaries. To monitor the changes in BMD in vivo dual-energy X-ray absorptiometry (DXA) was performed biweekly. After four weeks of treatment, animals were sacrificed for microCT and histological analyses.

Overall, these findings implied that systemic delivery of NELL-PEG in OVX mice would provide a novel strategy for osteoporosis therapy; nonetheless, further studies are needed to determine the optimum dosage and the efficacy of various routes of drug administration.

Keywords: NELL-1, PEGylation, osteoporosis, systemic osteogenic therapy