# Development of a novel therapy with Apolipoprotein E for osteogenesis imperfecta

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $164,851

## Abstract

Osteogenesis imperfecta (OI), known as a brittle bone disease, is a genetic disorder typically caused by a
mutation in type l collagen. In addition to bone fragility, growth deficiency is a critical musculoskeletal issue of
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, especially in patients with severe types of OI. Previously, we
and others have reported that systemic infusion of mesenchymal stem/stromal cells (MSC) can stimulate bone
growth in OI patients as well as in OI model mice. Despite this striking growth acceleration, the therapeutic
effects were transient. Moreover, MSC therapy has several inherent limitations such as inconsistent results
between different MSC donors, need for Good Manufacturing Practice facilities, and safety concerns of culture-
expanded cellular infusions. Thus, identifying the mechanism of MSC-induced bone growth is critical to
develop novel cell-free therapies that can be safely and repeatedly implemented during the growth period in OI
patients. Our investigation revealed that MSC-induced bone growth was not a direct effect of MSCs
themselves; rather, MSC infusion induced production of a factor(s) in the serum which stimulated chondrocyte
proliferation in the growth plate and resulted in linear bone growth. Proteomic and bioinformatics analyses of
the serum from MSC infused mice identified apolipoprotein E (ApoE) as a primary candidate for the factor. Our
preliminary studies demonstrated that ApoE serum levels were significantly elevated after MSC infusion and
recombinant ApoE markedly stimulated chondrocyte proliferation and hypertrophic differentiation in
chondrocyte culture. Moreover, ApoE enhanced bone growth in ex vivo organ culture. These findings were
strongly supported by compelling evidence that ApoE knockout mice display significantly shorter bones than
wild type mice. Collectively, these findings provide rigorous premises for our highly innovative hypothesis that
ApoE can improve bone growth deficiency by stimulating chondrocyte proliferation and differentiation in the OI
growth plate. Additionally, it has been shown that ApoE is produced by mature osteoblasts. In OI, mutated
Col1 expression prevents osteoblasts from maturation and as a result, the number of mature osteoblasts is
significantly reduced. Interestingly, our preliminary study showed that ApoE levels in bones were significantly
lower in OI mice than wild type controls. These findings suggest that reduced production of ApoE by OI
osteoblasts may play a critical role in the pathogenesis of OI growth deficiency. Thus, we propose the following
specific aims: (1) to determine the therapeutic effects of ApoE for growth deficiency in OI; and (2) to examine
the role of ApoE produced by osteoblasts in growth plate function and bone growth. The completion of these
aims will determine whether ApoE can serve as a novel therapeutic molecul...

## Key facts

- **NIH application ID:** 10262928
- **Project number:** 5R21AR077654-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Satoru Otsuru
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $164,851
- **Award type:** 5
- **Project period:** 2020-09-11 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10262928

## Citation

> US National Institutes of Health, RePORTER application 10262928, Development of a novel therapy with Apolipoprotein E for osteogenesis imperfecta (5R21AR077654-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10262928. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*