# Impact of TPO Treatment on Bone Healing and Angiogenesis in Type 2 Diabetes

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · —

## Abstract

Currently, 1 in 4 veterans receiving VA care is diabetic, and over 70% are overweight or obese and at
risk of developing diabetes. Diabetes is a risk factor for impaired fracture healing and numerous studies have
demonstrated increased frequency of non-union, partial union, or delayed union in diabetic patients as
compared to non-diabetic patients. Diabetic patients have impaired microcirculation which is partially
responsible for these fracture complications. In the case of non-union, additional interventions are required
such as bone grafting techniques.
 The gold standard for grafting to achieve bone union is the use of autograft from the patient's hip, which
may not always achieve healing. Additionally, the harvest of bone often leaves patients with a painful donor
site that may not resolve. Therefore, orthopaedic surgeons desire a biologic enhancement for bone healing
that does not require the harvesting of iliac crest bone. Local placement of bone morphogenetic proteins
(BMPs) is the only FDA approved biological option capable of healing non-unions. BMPs, although potent in
promoting bone regeneration, have been associated with several side effects, including a link with cancer.
Therefore, there is a great need for new therapies that heal bone with improved safety profiles. Recently, we
found that thrombopoietin [TPO, a megakaryocyte (MK) growth factor] could heal critical-sized bone defects in
mice, rats and pigs, as well as, if not better than, BMP-2. The long-term goal of this work is to determine
whether thrombopoietic agents could serve as novel therapies for bone healing.
 Our studies as well as the literature show that TPO increases pathways associated with angiogenesis,
increases hematopoietic cell populations, including osteoclasts (OCs) and MKs, and increases osteoblasts
(OBs) and bone formation, the latter is indirectly through MK-mediated OB proliferation. Based on these ideas,
we hypothesize that TPO accelerates bone healing in type 2 diabetes (T2D) by stimulating angiogenesis
which has the direct benefit of delivering mesenchymal and hematopoietic cells that mediate wound healing.
 In Aim 1, we will assess the therapeutic effects of TPO on bone healing in diet-induced obesity with
hyperglycemia, hyperinsulinemia, and glucose intolerance (T2D). Mice on a C57BL/6 background will be fed a
low fat diet (LFD) or a high fat diet (HFD), will undergo a segmental bone defect surgery, will be treated with
saline (negative control), BMP-2 (positive control), or TPO (experimental group), and bone healing assessed.
 In Aim 2, we will demonstrate the role of TPO in stimulating angiogenesis/vasculogenesis. This will be
accomplished by characterizing angiogenesis/vasculogenesis in mice from Aim 1, as well as in mice in which
the TPO receptor has been selectively knocked out of endothelial cells (ECs). We will also conduct a series of
in vitro studies to assess the impact of TPO treatment as well as secreted factors from MKs on EC function to
...

## Key facts

- **NIH application ID:** 9932901
- **Project number:** 5I01BX003751-04
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Melissa A Kacena
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932901

## Citation

> US National Institutes of Health, RePORTER application 9932901, Impact of TPO Treatment on Bone Healing and Angiogenesis in Type 2 Diabetes (5I01BX003751-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9932901. Licensed CC0.

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