Skeletal fracture is one of the most prevalent and costly medical issues in the United States, with direct costs exceeding $20 billion annually. In fact, some studies have shown that women over the age of 75 would rather be dead than suffer the consequences of a hip fracture. As a result, the overall goal of the Tomlinson lab is to determine novel mechanisms that augment bone strength and induce the rapid repair of skeletal fractures. In particular, the lab focuses on inflammatory signaling in the skeletal response to mechanical forces and damage using small animal models.
The Role of NGF-TrkA Sensory Nerve Signaling in Bone
Although sensory nerves are known to be present in mature bone, relatively little is understood about their function in the skeleton, aside from pain. In this project, we are investigating the role of NGF-TrkA signaling in sensory nerves. Nearly all of the nerves in bone express TrkA, the high affinity receptor for nerve growth factor (NGF). Furthermore, sensory nerves blanket the surfaces of bone in a mesh-like network, a privileged location for the acquisition of mechanical signals. Using both in vivo and in vitro methods, we have demonstrated that NGF is robustly expressed by mature osteoblasts in response to non-damaging mechanical loads. Inhibition of NGF-TrkA signaling impairs load-induced bone formation whereas administration of exogenous NGF increases relative bone formation rates. These effects appear to be facilitated through altered Wnt/β-Catenin signaling, which we are currently investigating by using mice which lack NGF in the osteoprogenitor and osteoblast lineages. In addition, we have identified a compound which may provide long-term activation of TrkA to increase load-induced bone formation without the painful side effects of NGF.
1. Tomlinson RE, Li Z, Zhang Q, Goh BC, Li Z, Thorek DL, Rajbhandari L, Brushart TM, Minichiello L, Zhou F, Venkatesan A, Clemens TL. “NGF-TrkA Sensory Nerve Signaling Coordinates Vascularization and Ossification of Bone”, Cell Reports 2016; 16(10):2723-35. PMCID: PMC5014649.
2. Tomlinson RE, Li Z, Li Z, Minichiello L, Riddle RC, Venkatesan A, Clemens TL. “NGF-TrkA Signaling in Sensory Nerves is Required for Skeletal Adaptation to Mechanical Loads in Mice”, Proceedings of the National Academy of Sciences 2017; 114(18):E3632-E3641. PMCID: PMC5422802.
NSAIDs in Stress Fracture Risk and Repair
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly consumed medication in the world, with over 30 million daily users in the United States alone. NSAIDs are effective in reducing pain and inflammation by preventing the synthesis of prostaglandin E2 (PGE2) through the blockade of the cyclooxygenase (COX) enzyme isoforms, COX1 and COX2. However, PGE2 is part of an inflammatory signaling pathway that is known to be critical for load-induced bone formation. In collaboration with our partners at the US Army Research Institute of Environmental Medicine and the Rothman Institute, we have identified a clear link between NSAID usage and stress fracture susceptibility. Furthermore, we have observed in mice that NSAIDs may increase stress fracture risk through two independent mechanisms – diminished load-induced bone formation and decreased bone toughness. In addition, we have identified NSAIDs which can provide analgesia without affecting stress fracture risk or repair. We are currently analyzing the mechanisms by which NSAIDs affect the skeleton, with the aim of uncovering novel therapeutic targets for relieving musculoskeletal pain without affecting bone health.
1. Park J, Restrepo CS, Parvizi J, Tomlinson RE. “Naproxen, but not Aspirin, Increases Risk and Impairs Repair of Stress Fractures”, 2017 Annual Meeting of the American Society for Bone and Mineral Research; Denver, CO, USA.
NSAIDs in Dental Implant Osseointegration
The use of dental implants has transformed the practice of dentistry over the last few decades. The success of this procedure relies on osseointegration, the process by which bone forms a structural and functional connection with the implant over a period of weeks to months. A significant portion of implants fail to osseointegrate, requiring additional surgical intervention. As a result, identifying factors that delay or prevent the osseointegration of dental implants is a top research priority. We hypothesize that use of NSAIDs in the immediate post-operative period may inhibit osseointegration of dental implants. This hypothesis may help explain idiopathic early failure of dental implants, since standard post-operative care often includes immediate and continuous use of high-dose NSAIDs. To directly test our hypothesis, we have assembled a research team of oral surgeons and orthopaedic basic scientists to generate quantitative data from newly placed dental implants as well as analyze bone tissue to ascertain the events that lead to early implant failure. This project is supported by an Osteo Science Foundation grant, in collaboration with our partners in Oral and Maxillofacial Surgery.
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