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Neuromedin-U (NMU) negatively regulates bone remodeling Público Deposited

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MLA citation style

Lowery, Jonathan, et al. Neuromedin-u (nmu) Negatively Regulates Bone Remodeling. . 1122. https://mushare.marian.edu/concern/generic_works/0cca2bb9-658f-4595-a14f-6788d079a3d0?locale=pt-BR

APA citation style

Lowery, Jonathan, Jackson, Krista, Zubosky, Tara, Hsiao, Yu-Tin, Squire, Maria, & Jestes, Kelli. (1122). Neuromedin-U (NMU) negatively regulates bone remodeling. https://mushare.marian.edu/concern/generic_works/0cca2bb9-658f-4595-a14f-6788d079a3d0?locale=pt-BR

Chicago citation style

Lowery, Jonathan, Jackson, Krista, Zubosky, Tara, Hsiao, Yu-Tin, Squire, Maria, and Jestes, Kelli. Neuromedin-U (nmu) Negatively Regulates Bone Remodeling. 1122. https://mushare.marian.edu/concern/generic_works/0cca2bb9-658f-4595-a14f-6788d079a3d0?locale=pt-BR

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Osteoporosis, a disease of low bone density that occurs when bone resorption ex-ceeds bone formation, places individuals at a higher risk for fracture and disability. We previously reported that deletion of the Bmpr2 gene in embryonic skeletal progenitor cells causes substantially elevated bone density in young adulthood and reduced age-related decline in bone density associated with elevated bone formation rate. Notably, bone-specific expression of the neuropeptide Neuromedin-U (Nmu) is inversely correlated with serum levels of the bone formation marker PINP in Bmpr2-cKO mice and a prior study reported global knockout of Nmu causes high bone mass. Together, these findings suggest that NMU, which is processed into two isoforms (NMU-8 and NMU-25) and signals via two GPCRs (NMU Receptor 1 (NMUR1) and NMU Receptor 2 (NMUR2)), is a negative regulator of osteoblast differentiation and/or activity. The molecular mechanism(s) by which these effects occur are unknown. Here, we provide secondary confirmation of a high bone mass phenotype in the absence of NMU func-tion, with tibiae BV/TV elevated 32% in 12-week-old female Nmu knockout mice (p-value=0.046). We additionally examine the bone-specific cell communication events that are associated with NMU-deficiency using high-throughput phospho-profiling anti-body arrays, which allow detection of ~300 targets using very small quantities of protein. This revealed decreased activation of the mTOR pathway in tibiae of Nmu knock-out mice compared to controls, with reduced activity-associated phosphorylation of mTOR and the mTOR target ribosomal protein S6. To begin establishing the skeletal NMU pathway, we determined that both Nmur1 and Nmur2 are expressed in bone and osteogenic cells. Cell-based in vitro assays indicate that NMU-25 reduces osteoblastic differentiation of W-20-17 murine bone marrow stromal cells (BMSCs) whereas NMU-8 has no effect on osteoblastic differentiation. In contrast, NMU-8 treatment of differenti-ated W-20-17 cells leads to increased proliferation whereas NMU-25 does not. Consistent with this, NMU-8 treatment of the osteoblast-like cell line MC3T3-E1 leads to increased proliferation and expression of alkaline phosphatase. Phospho-profiling ar-rays are currently underway to examine the mechanism(s) allowing for differential effects between NMU-8 and NMU-25 and the response of undifferentiated BMSCs versus osteoblastic cells. Collectively, our work highlights a novel factor associated with bone remodeling and may identify a new opportunity for treating low bone density in humans.

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