UCLA

Age-related osteoporosis is commonly associated with decreased bone mass, deterioration of bone microarchitecture, and increased bone marrow adipose tissue. Various risk factors and biological changes that occur with aging exponentially increase the prevalence of osteoporosis, which affects more than 200 million people worldwide. With the staggering biomedical burden, significant efforts have been made to explore new therapies that target the primary regulator of bone metabolism, the Wnt signaling pathway, and suppress PPARγ-mediated adipogenesis to enhance therapeutic efficacy. NELL-1 is a potent pro-osteogenic protein that has been well-characterized for its local and systemic bone-forming effects. Previously, we discovered that PEGylation of NELL-1 (NELL-PEG) significantly improved NELL-1’s bioactivities and potency for local and systemic use without inducing considerable biotoxicity. The current study seeks to explore the feasibility of NELL-PEG, with the combination of PPARγ suppression, as a more scientifically sophisticated osteoporosis therapy in which bone formation is promoted and lipid accumulation in the bone marrow is suppressed. We discovered that co-treatment with NELL-PEG and PPARγ suppression significantly enhanced the expression of the Wnt pathway, which led to increased bone formation and reduced bone resorption. In addition, the dual treatment strategy also suppressed the expression of PPARγ and CEBPa, which resulted in decreased bone marrow fat formation. Moreover, the dual treatment strategy was found to significantly enhance cell proliferation and reduce cell apoptosis. These findings prove the feasibility of NELL-1 for use in combination with other molecules in order to enhance the efficacy and safety profile of the co-treatment strategy. The feasibility and readiness of the NELL-1 protein to be modified and used in combination with other molecules, without inducing undesirable side effects, is one of NELL-1’s unique features, in addition to its pro-osteogenic, anti-osteoclastic, and anti-adipogenic properties. In conclusion, optimizing the novel combination of a NELL-1-based therapy with a PPARγ suppressor could be crucial for facilitating long-term drug formulations that have improved efficacy and safety profiles. This development could serve as a novel platform that can be applied to other Wnt-ligand targeting therapies for the purpose of improving the efficacy and safety profile of current standard of care for osteoporosis.