# Mechanism of growth deficiency in dominant forms of osteogenesis imperfecta

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $339,900

## Abstract

PROJECT SUMMARY
Osteogenesis imperfecta (OI), known as a brittle bone disease, is a genetic disorder typically caused by
autosomal dominant mutations in one of the two genes that encode type l collagen (Col1). In addition to bone
fragility, growth deficiency is a critical musculoskeletal issue in OI. There is no cure for OI. While
bisphosphonates are the standard treatment to strengthen bones, there is no reliably effective treatment for
growth impairment. One of the major hurdles preventing the development of such treatments is that the
mechanism of how a mutation in Col1 causes growth deficiency has not been elucidated. Given that
treatments to improve osteoblast function were not effective for resolving bone length deficiency, cell types
other than osteoblasts might be involved in OI growth retardation. We and others found abnormalities in the
growth plate, where longitudinal bone growth occurs, including increased total height, decreased chondrocyte
turnover and fewer proliferating chondrocytes, suggesting that mutated Col1 somehow affects chondrocytes in
the growth plate. Thus, understanding the mechanism underlying chondrocyte defects is critical to develop
treatments for OI growth deficiency. In this proposal, we will focus on dominant OI using G610C mice
harboring Col1 mutation because 85-90% of OI are autosomal dominant forms. Our data demonstrated that OI
HCs began to express Col1 as they mature along with the enlarged endoplasmic reticulum (ER), suggesting
that OI HCs are exposed to higher ER stress similar to OI osteoblasts. Our preliminary studies demonstrated
that G610C OI chondrocytes had a lower ability to express hypertrophic phenotypes in pellet cultures and an
ER stress reducer ameliorated this defect, suggesting that ER stress may cause dysfunction not only in
osteoblasts but also in HCs in OI. Indeed, it has been shown that induction of ER stress in HCs causes HC
dysfunction and results in growth deficiency. Collectively, these findings provide rigorous premises for our
highly innovative hypothesis that HC dysfunction induced by ER stress plays a pivotal role in growth deficiency
of dominant OI. This hypothesis will be addressed by experiments supporting the following specific aims: (1) to
characterize ER stress occurring in HCs in G610C OI mice, (2) to determine HC dysfunction in G610C OI
mice, and (3) to determine ER stress in HCs from dominant OI patients with distinct mutations. The completion
of these aims will determine whether growth deficiency in dominant OI is a consequence of HC dysfunction
caused by ER stress. The outcome of this innovative project has potential to change our understanding of OI
by redefining OI not only as “bone disease” but also as “cartilage disease”, and by providing approaches
focused on chondrocytes, rather than osteoblasts or osteoclasts in developing therapeutic strategies for growth
impairment in OI.

## Key facts

- **NIH application ID:** 9969787
- **Project number:** 1R01AR075733-01A1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Satoru Otsuru
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,900
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969787

## Citation

> US National Institutes of Health, RePORTER application 9969787, Mechanism of growth deficiency in dominant forms of osteogenesis imperfecta (1R01AR075733-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9969787. Licensed CC0.

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