# The Nmp4 Anti-Anabolic Bone Axis R01AR070144-01A1

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $428,267

## Abstract

“The holy grail of osteoporosis therapy remains the restoration of … bone mass…”, and consequent fracture
reduction. Current osteoporosis therapies have significant limitations and NIAMS objectives include
addressing “why some therapeutic agents become less effective with long-term use and “exploring
opportunities for discovery of newly identified molecular targets for new drug treatments”. Mice harboring a
loss-of-function mutation in the gene encoding the transcription factor Nmp4 are healthy, long-lived, and
exhibit an unremarkable skeletal phenotype until challenged with an anabolic stimulus including several
classes of osteoporosis therapies, which elicits enhanced bone formation. The absence of a baseline
phenotype, combined with the improved response to therapy, affords a unique advantage for developing Nmp4
(or one of its upstream/downstream components) as a safe target to enhance efficacy of existing therapies and
identify molecular targets for new therapies. Our goal is to determine how disabling Nmp4 improves the
osteoanabolic response to drug treatments, in order to distinguish targetable molecules that can be translated
to patients. Our published and preliminary –omic, biochemical, and bone mechanical data inform our
hypothesis that Nmp4 limits the number of osteoprogenitors and regulates the composition, production, and
export of the matrix and ultimately bone mechanical properties. Furthermore, loss of Nmp4 in osteogenic cells
sharply enhances global mRNA translation, coincident with induction of select portions of the unfolded
protein response (UPR), which serve to expand the processing capacity of the ER and facilitate protein
secretion, converting the osteoblast into a super-secretory cell. We propose that these super-secretors
release a disproportionately high level of osteocalcin and osteopontin that contribute to the formation of
fracture resistant bone. Three independent aims will reveal the mechanisms underlying Nmp4 action.
Aim #1: identify the specific cell type(s) driving the Nmp4-/- response to anabolic agents. Ovariectomized mice
harboring selective genomic deletion (flox) of Nmp4 from MSPCs, osteoblasts, or osteoclasts will be treated
with mono- and combination osteoporosis therapies. To target the Nmp4 pathways for pharmacological
intervention it is crucial to identify the cell type driving the beneficial effects. Aim #2: determine how Nmp4
regulates osteoblast ribosome biogenesis, global and gene-specific mRNA translation rates of matrix proteins,
and strategic portions of the UPR coincident with control of ER expansion. The UPR pathway is a potential
therapeutic target for numerous disorders including osteoporosis. Aim #3: determine the matrix and
mineral composition of the Nmp4-/- bone in the context of energy dissipation mechanisms subsequent to
fatigue and fracture toughness tests. Completion of this aim will provide perspectives into the relationship
between the osteoblast secretome and bone material properties...

## Key facts

- **NIH application ID:** 10232333
- **Project number:** 5R01AR073739-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** JOSEPH P BIDWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $428,267
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232333

## Citation

> US National Institutes of Health, RePORTER application 10232333, The Nmp4 Anti-Anabolic Bone Axis R01AR070144-01A1 (5R01AR073739-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10232333. Licensed CC0.

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