# Regulation of Osteoblast Metabolism by Lrp5

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

Abstract
Since the identification of causative mutations in Lrp5 in osteoporosis-pseudoglioma and the high bone mass
syndrome, the low-density lipoprotein receptor-related protein 5 (Lrp5) has been firmly linked with osteoblast
function in humans and animal models. In the previous funding period, we demonstrated that Wnt/b-catenin
signaling through Lrp5 regulates long-chain fatty acid utilization by the osteoblast. Thus, transgenic mice
lacking Lrp5 specifically in the osteoblast exhibited an increase in adipose tissue mass and developed a
dyslipidemia in addition to the expected low bone mass phenotype. Moreover, genetic ablation of Cpt2, an
obligate enzyme in long chain fatty acid catabolism, in the osteoblast impairs bone acquisition and led to an
increase in serum lipids. Together, these data suggest that bone is a site of significant fatty acid utilization and
that the regulation of osteoblast metabolism by Lrp5 contributes to both bone accrual and whole body energy
balance. In this renewal application we will use genetic mouse models to (1) determine the mechanism by
which fatty acids are acquired by the osteoblast and (2) assess the metabolic substrate requirements that are
necessary for Wnt-stimulated bone formation. We hypothesize that fatty acid uptake will require the actions of
Slc27a1 and/or CD36 and that inhibition of fatty acid utilization will be sufficient to inhibit the Wnt-induced
increase in bone formation associated with Sost deficiency or expression of a Lrp5 high bone mass allele.
These studies will further our understanding of the metabolic requirements of bone formation, the contribution
of bone to metabolism, and the mechanisms by which Wnt/b-catenin signaling govern skeletal homeostasis.

## Key facts

- **NIH application ID:** 9902408
- **Project number:** 5R01DK099134-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Ryan C Riddle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2013-07-24 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902408

## Citation

> US National Institutes of Health, RePORTER application 9902408, Regulation of Osteoblast Metabolism by Lrp5 (5R01DK099134-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902408. Licensed CC0.

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