Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Gender Differences in Heterotopic Ossification
Kavitha Ranganathan, M.D., Jonathan Peterson, BS, Oluwatobi Eboda, BS, Shailesh Agarwal, MD, Steven Buchman, MD, Paul Cederna, MD, Stewart Wang, MD, PhD, Benjamin Levi, MD
University of Michigan Health Systems, Ann Arbor, MI, USA.

PURPOSE: The ectopic formation of bone within soft tissue structures, or heterotopic ossification (HO), has been shown to occur most commonly in patients suffering from burn injuries, prolonged periods of immobilization, and trauma. Previous studies have quoted male gender as a risk factor in the development of HO. It remains unclear why males are more predisposed to this pathology as compared to females. In this study, we explore differences in ectopic bone formation between male and female mice in the setting of burn and non-burn models to quantify and characterize differences in heterotopic ossification.
METHODS: An Achilles tenotomy and burn model was used to study the in vivo and in vitro relationship between gender and heterotopic ossification. Mice were divided into burn and non-burn groups with 3 male or 3 female mice in each of the four groups. All mice received an Achilles tenotomy and micro-CT scans were performed at 5, 7, and 9 weeks to quantify the extent of heterotopic ossification in each group. Histology was performed following the course of uCT scans. In vitro, adipose-derived mesenchymal cells (MSCs) capable of forming bone were harvested from both male and female mice in burn and non-burn control groups. Each cell type was exposed to osteogenic differentiation media (ODM) and the osteogenic potential assessed by alkaline phosphatase and alizarin red stain and quantification. Osteogenic transcripts and proteins were assessed by qRT PCR and Western Blot analyses.
RESULTS: 3 male and 3 female mice were utilized in each burn and non-burn group. Female mice in the burn group formed less bone as compared to male mice in the burn group as quantified on CT scan at 5, 7, and 9 weeks. An average of 4.9 mm3 of ectopic bone formed following burn injury in female mice compared to 6.6 mm3 in male mice with burn injury (p<.05). Similarly, MSCs derived from male mice in the burn group were much more osteogenic in comparison to MSCs derived from female mice in the burn group at 2 hours (p<.05). A similar relationship between male and female quantities of bone formation was noted in the non-burn group at this time point.
CONCLUSIONS: We demonstrate that male mice form quantitatively more bone as compared to female mice based on data from micro-CT scans and histology immediately after Achilles tenotomy. Furthermore, MSCs derived from male mice in the burn group were more osteogenic than MSCs derived from their female counterparts. Going forward, we aim to identify the exact mechanism behind differences in HO formation between males and females so that such differences can be exploited to develop novel therapeutics.


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