SUMMARY Veterans with fractures suffer from injury-associated pain as well as post-operative surgical pain. The occurrence of a fracture contributes to acute pain and is largely manifested by mechanical, inflammatory, and neuropathic components. The LEAP study of high-energy lower extremity trauma showed that acute pain, in the recovery period after severe trauma, is the single largest predictor of long-term chronic pain 5-10 years after injury. There are 2 main strategies to treat trauma-induced and post-surgical pain: opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Neither drug class completely alleviates pain, and both have negative side effects. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. NSAIDs are commonly used in combination with opioids following thoracic/abdominal surgery but use of this drug class for fracture pain is discouraged in the U.S. due to negative effects on skeletal health and healing of the injured skeleton. It is unclear which drug class is less destructive to the bone repair process but prevention of nonunion is paramount in the treatment of fractures as it places additional burden on the patient and the healthcare system due to prolonged pain and disability. Therefore, identification of therapies which improve both the bone healing process and diminish the fracture-associated pain is warranted. Our group has previously shown that the main megakaryocyte (MK) growth factor, thrombopoietin (TPO), can improve bone healing. In preliminary studies we demonstrate that fracture targeting thrombopoietin mimetic peptides (TMPs) also markedly improve fracture healing, and that high levels of platelet derived growth factor (PDGF) are observed at the fracture site with TMP treatment. As both osteoblasts (OBs) and endothelial cells (ECs) express the receptor for PDGF (PDGFRβ), actions of PDGF on these cells could be responsible for the improvements in bone healing observed. On the other hand, PDGF expression is also known to increase pain behaviors, and PDGFRβ is also expressed on sensory neurons. Based on these observations we hypothesize that short-term administration of TMP will increase PDGF at the fracture site, stimulating OB and EC activity, leading to accelerated bone healing. Because inhibition of the PDGF-PDGFRβ axis has been shown to attenuate pain behaviors, we further hypothesize that inhibition of PDGFRβ-signaling subsequent to the inflammatory phase of fracture healing, at 8-30 days post-surgery, will decrease chronic pain and inflammation without compromising fracture healing. Three specific aims will address this hypothesis. In Aim 1, we will determine if systemic versus targeted TMP can accelerate post-fracture bone healing and reduce inflammation and pain behaviors. In Aim 2, we will determine if PDGFRβ signaling in OBs and/or ECs is required for TMP-stimulated bone healing. In Aim 3, we will determine if inhibiting PDGFRβ-signaling following TMP t...