# Molecular Regulatory Mechanism of Calvaria Bone Development and Homeostasis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $365,750

## Abstract

Human linkage studies have shown that genetic mutations related to cholesterol metabolism and high maternal
cholesterol diets result in craniofacial bone deformities, suggesting that cholesterol metabolic aberrations may
be a widely conserved mechanism in craniofacial developmental defects. However, it is still largely unknown
how altered cholesterol metabolism causes craniofacial bone abnormalities. Therefore, the objective of this
application is to define how cholesterol metabolic aberrations, through disruption of either the Dhcr7 gene
(which encodes an enzyme involved in the last step of cholesterol synthesis and is the causative gene for
Smith-Lemli-Opitz syndrome) or the Insig1 and Insig2 genes (which provide instructions for endoplasmic
reticulum proteins that regulate lipid biosynthesis), cause osteoblast (OB) differentiation abnormalities, and to
test the functional significance of downstream target molecules during craniofacial bone formation. The long-
term goal of this project is to gain insight into the mechanisms of craniofacial bone formation and provide new
medications and diagnostic tools for bone diseases. We will test our working hypothesis by using mouse
genetics and cellular biology approaches. In our preliminary studies, we found that: 1) impaired cholesterol
synthesis resulted in accelerated bone formation; 2) excess cholesterol synthesis resulted in decreased bone
formation; 3) the formation of primary cilia, which play a crucial in sensing cell signals, was altered in OBs from
Dhcr7 knockout (KO) and neural crest specific Insig1/2 conditional knockout (cKO) mice; 4) WNT signaling was
altered in Dhcr7 KO and Insig1/2 cKO mice; and 5) normalization of cholesterol metabolic aberrations restored
craniofacial bone defects in Dhcr7 KO and Insig1/2 cKO mice. Our hypothesis that proper cholesterol
metabolism is crucial for normal craniofacial bone formation will be tested in the following specific aims: 1) to
determine the role of cholesterol metabolism in craniofacial bone development; and 2) to determine the role of
cholesterol metabolism in primary cilium formation in bone. This study will unravel a new mechanism of bone
development and homeostasis and will lead to innovative methods of diagnosis, treatment, and prevention of
skull deformities.

## Key facts

- **NIH application ID:** 10133045
- **Project number:** 5R01DE026767-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Junichi Iwata
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133045

## Citation

> US National Institutes of Health, RePORTER application 10133045, Molecular Regulatory Mechanism of Calvaria Bone Development and Homeostasis (5R01DE026767-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10133045. Licensed CC0.

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