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NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy

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The skeleton is a secretory organ, and the goal of some osteoporosis therapies is to maximize bone matrix output. Nmp4 encodes a novel transcription factor that regulates bone cell secretion as part of its functional repertoire. Loss of Nmp4 enhances bone response to osteoanabolic therapy, in part, by increasing the production and delivery of bone matrix. Nmp4 shares traits with scaling factors, which are transcription factors that influence the expression of hundreds of genes to govern proteome allocation for establishing secretory cell infrastructure and capacity. Nmp4 is expressed in all tissues and while global loss of this gene leads to no overt baseline phenotype, deletion of Nmp4 has broad tissue effects in mice challenged with certain stressors. In addition to an enhanced response to osteoporosis therapies, Nmp4-deficient mice are less sensitive to high fat diet-induced weight gain and insulin resistance, exhibit a reduced disease severity in response to influenza A virus (IAV) infection, and resist the development of some forms of rheumatoid arthritis. In this review, we present the current understanding of the mechanisms underlying Nmp4 regulation of the skeletal response to osteoanabolics, and we discuss how this unique gene contributes to the diverse phenotypes among different tissues and stresses. An emerging theme is that Nmp4 is important for the infrastructure and capacity of secretory cells that are critical for health and disease.

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Acknowledgements

This work was supported by National Institutes of Health grants R01 AR073739 to JPB and R01 AR053237 to AGR; VA grants I01 BX005861 and IK6 BX 003783 to AGR; and support from T32 AR065971 to EGA and CK.

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Authors and Affiliations

  1. Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, 46202, USA

    Crystal Korff

  2. Department of Anatomy, Cell Biology & Physiology, IUSM, Indianapolis, IN, 46202, USA

    Emily Atkinson, Michele Adaway, Angela Klunk, Alexander G. Robling & Joseph P. Bidwell

  3. Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA

    Ronald C. Wek

  4. Center for Biotechnology & Interdisciplinary Studies and Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    Deepak Vashishth

  5. Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN, 46202, USA

    Joseph M. Wallace

  6. Indiana Center for Musculoskeletal Health, IUSM, Indianapolis, IN, USA

    Joseph M. Wallace, Alexander G. Robling & Joseph P. Bidwell

  7. Department of Pediatrics and the Herman B Wells Center for Pediatric Research, IUSM, Indianapolis, IN, USA

    Emily K. Anderson-Baucum & Carmella Evans-Molina

  8. Center for Diabetes and Metabolic Disease and the Wells Center for Pediatric Research, IUSM, Indianapolis, IN, USA

    Carmella Evans-Molina

  9. Richard L. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA

    Carmella Evans-Molina & Alexander G. Robling

  10. Department of Medicine, IUSM, Indianapolis, IN, USA

    Carmella Evans-Molina

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Korff, C., Atkinson, E., Adaway, M. et al. NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy. Calcif Tissue Int 113, 110–125 (2023). https://doi.org/10.1007/s00223-023-01088-x

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