# Exposing Invisible Wounds: Impacts of PTSD on Bone Health

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Post-traumatic stress disorder (PTSD) is 3-4 times more prevalent in Veterans than in the general population,
and this disparity is anticipated to increase due to heightened awareness, better diagnostic procedures, extension
of ongoing conflicts, and prolonged, repeated deployments. PTSD has been described as a life sentence due to
its association with increased risk of chronic disease, accelerated aging, and premature mortality. Most studies to
date have focused on understanding the direct impacts of PTSD on mental health. Only recently has attention
shifted to understanding the comorbidities that lead to this life sentence. Meta analyses suggest that low bone
mass (osteopenia) and osteoporosis are significant comorbidities for patients with PTSD. Thus, identification of
PTSD-related risk and subsequent mechanisms for the development of low bone mass disease is critical and
highly relevant to providing comprehensive health care for our Veterans.
 To begin to address this growing health concern, we have established a murine model that exhibits key clinical
DSM-5 characteristics of PTSD, including intrusiveness, avoidance, hyperarousal, and lasting symptoms. Using
this preclinical model, we have shown that mice with a PTSD-like phenotype exhibit trabecular bone loss and
decreased mechanical properties. Mechanisms driving this bone loss are unclear; however, our preliminary data
implicate inflammation and the ubiquitously expressed src homology 2-containing protein tyrosine phosphatase 2
(SHP2) as drivers of PTSD-associated bone loss. SHP2 has been shown to integrate multiple signaling events
across a variety of physiological and pathological functions, including inflammation, to regulate PI3K/AKT and
MEK/ERK signaling. In our model of PTSD, we show SHP2 expression is increased in bone and that inhibition of
SHP2 results in increased osteogenesis and decreased osteoclastogenesis in vitro and improved bone health in
mice with PTSD in vivo. Based on these data, Specific Aims will test the hypothesis that PTSD negatively impacts
bone health through SHP2-mediated regulation of osteogenesis and osteoclastogenesis. Aim 1 will uncover
cellular mechanisms by which PTSD alters osteoblast-osteoclast balance to promote bone loss. Clinically-relevant
readouts will be used to determine the comprehensive impact of PTSD on bone health. Based on our identification
of hematopoietic stem cell (HSC)-derived osteoprogenitors, studies will evaluate if PTSD differentially affects
osteoblastogenesis and osteoclastogenesis from multiple progenitors to lead to observed bone phenotypes. As
inflammation has been shown to play a significant role in disrupting osteoclast-osteoblast equilibrium, the role of
inflammation in PTSD-related bone loss will also be examined. Aim 2 will define mechanistic roles of SHP2 in
PTSD-driven bone loss. This aim will determine the impact of SHP2 inhibition on progenitor cell, osteoblast, and
osteoclast survival, proliferation, differentiation/m...

## Key facts

- **NIH application ID:** 10720880
- **Project number:** 5I01BX005168-02
- **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:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10720880

## Citation

> US National Institutes of Health, RePORTER application 10720880, Exposing Invisible Wounds: Impacts of PTSD on Bone Health (5I01BX005168-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10720880. Licensed CC0.

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