# Osteocytes in osteogenesis imperfecta (OI)

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $294,195

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 2
 Osteogenesis imperfecta (OI) is usually caused by mutations in type I collagen genes and more rarely, by
recessive mutations in genes involved in type I collagen processing (e.g., CRTAP). Because type I collagen is
the most abundant matrix component secreted by bone forming osteoblasts, these cells have been considered
the primary mediators of the disease presentation. Consequently, a possible role for osteocytes in the skeletal
manifestations of OI has largely been overlooked. Thus, the overall goal of Project 2 is to elucidate the
contribution of osteocytes to bone fragility in OI and identify changes in the osteocytic transcriptome that may
lead to new therapeutic targets. Our preliminary data show that osteocytes express as much type I collagen as
osteoblasts, suggesting that alterations in type I collagen, in addition to affecting osteoblasts, may also negatively
impact osteocytes. In support of this, we found that the osteocyte transcriptomes from 2 mouse models of OI
were significantly dysregulated compared to control mice. Moreover, osteocytes actively express all 19 genes
associated with dominant and recessive forms of OI. However, it is unknown to what extent altered collagen in
OI affects the function of osteocytes, and whether their transcriptional dysregulation is a direct consequence of
the altered collagen expressed by osteocytes or due to their interaction with altered collagen produced by
osteoblasts. Our central hypothesis is that osteocytes contribute to the bone fragility observed in OI and that
expression of altered type I collagen in osteocytes disrupts osteocyte function and, in turn, alters the osteocytic
expression of genes that regulate bone homeostasis. To test this hypothesis, we generated a novel knock-in
mouse model in which Cre-mediated recombination can be used to express an OI glycine substitution
(p.Gly1146Arg) mutation in the endogenous Col1a1 gene. We will breed this mouse with EIIa-Cre and Sost-Cre
mice, to express the mutation globally or specifically in osteocytes, and then compare the skeletal phenotype of
offspring using dual X-ray absorptiometry, micro-CT, bone biomechanics, bone histomorphometry, and Q-PCR
to assess what aspects of the OI skeletal phenotype are reproduced in osteocyte-specific knock-in OIOCY mice
(Aim 1). We will also generate a conditional allele for a collagen-modifying gene (Crtap) and determine the
skeletal consequences of its deletion in osteocytes versus global inactivation using the methodologies described
above (Aim 2). To determine if osteocyte function in OI is affected because they express abnormal collagen,
because they interact with a defective bone matrix secreted by osteoblasts, or both, we will identify osteocyte
transcriptome differences between osteocyte-specific Crtap KO, global Crtap KO, and WT mice using both bulk
and single-cell RNA-seq (Aim 3). These studies will provide direct evidence of the extent to which altered
collagen a...

## Key facts

- **NIH application ID:** 10495748
- **Project number:** 2P20GM125503-06
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** ROY MORELLO
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $294,195
- **Award type:** 2
- **Project period:** 2018-02-16 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495748

## Citation

> US National Institutes of Health, RePORTER application 10495748, Osteocytes in osteogenesis imperfecta (OI) (2P20GM125503-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10495748. Licensed CC0.

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