# Regulation of osteocalcin secretion and its therapeutic implication

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $551,286

## Abstract

Project Summary – Project #1
The number and diversity of the physiological processes regulated by the bone-derived hormone osteocalcin
raise the question of the regulation of osteocalcin secretion in vivo. Moreover, the fact that circulating levels of
osteocalcin decrease so steeply in mice, horses, monkeys, and humans relatively early during life raises the
question as to whether increasing circulating levels of this hormone in older animals could correct at least in
part, manifestations of aging affecting the physiological process regulated by osteocalcin. In support of this
hypothesis, we have already gathered evidence that osteocalcin can indeed rescue the age-related decrease
in muscle functions and cognitive functions. To address in a more global manner the questions presented
above we searched for a regulator of osteocalcin secretion whose biology could be harnessed to demonstrate
that increasing osteocalcin secretion could correct some deleterious manifestations of aging. In performing
this endeavor we have accumulated strong preliminary evidence that neuron-derived glutamate enters
osteoblasts and, through competitive inhibition of the gamma-glutamyl carboxylase, allows the release of
uncarboxylated osteocalcin from osteoblasts. We now want to 1) demonstrate the cell-specificity nature of this
mechanism, 2) test whether this mechanism can be harnessed to rescue at least in past manifestations of
aging caused by a decrease in the physiological functions that osteocalcin normally enhance. To achieve
these overlapping goals the Specific Aims of this application are:
 Establish in vivo that it is through its expression in cells of the osteoblast lineage that Glast influences
 the release of the uncarboxylated form of osteocalcin in the general circulation.
 Test whether overexpressing Glast in osteoblasts or osteocytes would improve energy expenditure,
 glucose metabolism, adaptation to exercise, cognitive functions and fertility in aging mice by favoring
 OCN release.

## Key facts

- **NIH application ID:** 10024563
- **Project number:** 2P01AG032959-11A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gerard Karsenty
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $551,286
- **Award type:** 2
- **Project period:** 2010-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024563

## Citation

> US National Institutes of Health, RePORTER application 10024563, Regulation of osteocalcin secretion and its therapeutic implication (2P01AG032959-11A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10024563. Licensed CC0.

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