Editors' ChoiceBONE FORMATION

“TrkA”cking why “no pain, no gain” is the rule for bone formation

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Science Translational Medicine  10 May 2017:
Vol. 9, Issue 389, eaan3780
DOI: 10.1126/scitranslmed.aan3780

Abstract

Peripheral sensory nerves expressing TrkA innervate long bones and stimulate bone formation through the Wnt/β-catenin pathway when placed under stress.

Anyone who has broken a bone or even suffered a stress fracture knows the associated intense pain. Although most people would prefer not to have this pain, as the saying goes: no pain, no gain… in bone mass, that is. A recent study by Tomlinson and colleagues demonstrates the role that thinly myelinated or unmyelinated sensory nerves expressing neutrotrophic tyrosine kinase receptor (TrkA) play in the response of bone to mechanical stress. It was known that patients with congenital insensitivity to pain with anhidrosis (CIPA) have skeletal disorders. However, the interaction between sensory nerves and the response of bone to mechanical stress has not been previously defined.

Tomlinson et al. employed a novel animal system that uses a small molecule to inhibit TrkA. Mice were subjected to axial compression of the upper extremity, which produced an expected anabolic response and increased bone formation on the periosteal and endosteal bone surfaces. Mice with inhibition of TrkA signaling, however, had a significantly diminished anabolic response and less bone formation. Next, they showed that under stress, osteoblasts produced nerve growth factor (NGF), whereas nonstressed osteoblasts did not secrete NGF. They also demonstrated that this osteoblast-secreted NGF stimulated nerve sprouting, defining an interesting cross-talk between the skeletal and nervous systems. To elucidate the pathway by which TrkA might alter the skeletal response to stress, the authors used a canonical Wnt reporter mouse and established an increase in Wnt signaling with stress that was tempered by TrkA inhibition. Last, they found a dramatic increase in the anabolic bone response with load-induced stress by administering exogenous NGF.

This study further defines the important interaction between sensory nerves and cells on the periosteal and endosteal surfaces of bone. The positive role of sensory nerves in the response of bone to stress may give clinicians pause prior to prescribing medications for musculoskeletal pain, as they may impair bone maintenance and repair. Based on these findings, researchers have a potential new target, TrkA, to combat age-related bone loss and bone disease and to augment fracture healing.

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