Targeting Lymphatics to Treat Trauma-Induced Heterotopic Ossification

The proposed project directly relates to the FY20 PRMRP Topic Area of Musculoskeletal Health, and Area of Encouragement 'Research to better understand tissue-specific diseases or injuries (e.g., bone, cartilage, tendon, and/or muscle) with a focus on treatment, recovery, or regeneration.'

Heterotopic ossification (HO) is the abnormal growth of bone in non-skeletal tissues after trauma. Patients with HO may have difficulty performing normal daily activities because they have decreased range of motion of involved joints or suffer from severe debilitating pain. HO is caused by aberrant tissue repair and is a common complication of trauma. Extremity trauma coupled with a bone fracture is a common form of injury in military personnel and confers an increased risk of HO. The prevalence of HO is further increased in patients with a combination of musculoskeletal trauma and large surface-area burns, which is frequently seen in the setting of blast injuries. Current treatments for HO include nonsteroidal anti-inflammatory drugs (NSAIDs) and surgery. However, these treatments are inadequate for many patients. Therefore, there is an urgent need for new therapies to prevent HO formation and reverse existing HO lesions.

In this application, we propose to investigate the role lymphatic vessels serve in HO formation. Lymphatic vessels collect and drain fluid lost by blood vessels, absorb dietary fats, and transport immune cells to lymph nodes. Lymphatics are in most regions of the human body, and they form a rich network of vessels around bones. There is growing evidence that the immune system serves a critical function in the formation and progression of HO. However, the precise role lymphatic vessels serve in pathophysiology of HO is poorly understood. Filling this gap in knowledge could lead to new and novel treatments for HO. By studying a mouse model of trauma-induced HO, we discovered that HO progenitor cells express a high level of a factor that induces the growth of lymphatics. We also found that mice engineered to overexpress a lymphatic growth factor in bone develop lymphatics within bone and gradually lose bone. Based on our preliminary data, we hypothesize that post-traumatic lymphatic formation and signaling can be targeted pharmacologically or surgically to mitigate HO formation and progression and reverse existing HO lesions. To test this hypothesis, we will use genetic approaches to either inhibit or induce lymphatic growth around HO lesions in mice (Aim 1). We will then examine the effect of these manipulations on HO formation and regression. We will also test the effect of a drug that inhibits lymphatic development, and of a common surgical procedure that impairs lymphatic drainage, on HO formation in mice (Aim 2).

There is limited research on the fundamental biology that governs HO. This has made it challenging to develop logical new therapeutic agents. The present proposal will comprehensively determine the requirement of lymphatics in HO, with an end goal of developing a near clinical therapeutic and surgical intervention to improve outcomes after extremity trauma. Importantly, our pharmacological and surgical interventions offer novel, readily translatable, and easily deployable treatments to improve extremity trauma recovery, return to duty, and rehabilitation. This work could change the current paradigm for HO research and have a significant biomedical impact on other patients who suffer from complications associated with aberrant wound repair.