# Potential of Hematopoietic Stem Cell-Based Therapies for Complicated Fractures

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2021 · —

## Abstract

Musculoskeletal extremity injuries comprise ~50% of all combat wounds for OIF/OEF/OND Veterans. Blast
injuries via improvised explosive devices account for over 75% of combat casualties, with survivors
experiencing severe orthopedic injuries. These types of orthopedic injuries often result in delayed or non-union,
wherein normal bone healing is impaired. Current interventions for non-union fractures, particularly atrophic
non-union fractures are rarely successful. OIF/OEF/OND Veterans are also at a high risk for depressive and
depressive-associated disorders including post-traumatic stress disorder (PTSD), resulting in >60% of this
population being prescribed antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs). While
the effects of SSRIs on fracture healing are unknown, it has been shown that Sertraline (Zoloft) and Paroxetine
(Paxil), first-line SSRIs for pharmacological treatment of these disorders, negatively affect bone health. Given
the prevalence of complex orthopedic injuries, the long-term complications from these injuries, and the
commonness of SSRI use in the OIF/OEF/OND Veteran population, there is a need for new therapies (e.g.,
cell-based therapies) that may overcome current clinical limitations for complicated fractures.
 Our studies using a unique clonal cell transplantation model in conjunction with murine fracture models has
identified the hematopoietic stem cell (HSC) as a novel progenitor for osteoblasts, osteocytes, and
chondrocytes during fracture repair. Recent studies show HSC-derived osteoprogenitors directly give rise to
bone in vivo. These findings are paradigm shifting in that most studies focus on the use of mesenchymal stem
cells (MSCs) for musculoskeletal injury repair and suggest a benefit of HSC-based therapies for complicated
fracture. Building on our previous MERIT studies, which demonstrated a role for bone morphogenetic protein-2
(BMP-2), BMP-9, and insulin-like growth factor (IGF-2) in promoting osteogenesis from the HSC, we have now
shown a combination of IGF-2+BMP-9 results in enhanced osteoinduction from HSC-osteogenic precursors.
We have also identified HSC-derived circulating osteogenic progenitors (COPs) that increase in blood during
normal fracture repair and are mobilized with AMD3100 delivery, suggesting a potential therapeutic modality.
Our preliminary data also demonstrate that SSRI administration in vivo leads to impaired bone healing, results
in altered osteogenic profiles during healing, and inhibits osteoinduction from HSC-progenitors in vitro.
 We hypothesize that HSC-derived osteo-chondrogenic progenitor cells may be targeted to enhance repair
of complicated fractures. Our goals are to examine the ability of HSC-derived osteo-chondrogenic progenitors
(compared to MSCs) to serve as a therapeutic modality during complicated non-union fractures and fractures
during SSRI administration, uncover the mechanisms by which these cells may have a beneficial effect, and
elucidat...

## Key facts

- **NIH application ID:** 10045563
- **Project number:** 5I01BX000333-11
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** AMANDA C. LARUE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045563

## Citation

> US National Institutes of Health, RePORTER application 10045563, Potential of Hematopoietic Stem Cell-Based Therapies for Complicated Fractures (5I01BX000333-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10045563. Licensed CC0.

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