Osteoblast-derived nerve growth factor supports skeletal adaptation to mechanical load and the osteoanabolic effect of gambogic amide in mice.

Abstract

In adult mice, new bone accrual following mechanical load is mediated by the neurotrophin nerve growth factor (NGF) that is expressed by osteoblasts on the bone surface. NGF can bind to its high affinity receptor, neurotrophic tyrosine kinase receptor type 1 (TrkA), on peripheral sensory nerves resident in bone and support new bone formation. However, the osteoanabolic therapeutic potential of NGF-TrkA signaling to repair bone is limited due to the long-lasting thermal and mechanical hyperalgesia induced by administration of NGF in mice and humans. Here, we investigated whether 1) mature osteoblasts are the primary source of NGF required for bone accrual following loading, and 2) a small molecule TrkA receptor agonist - gambogic amide - can harness the downstream osteoanabolic potential of NGF-TrkA signaling in the absence of endogenous NGF. Loss of Ngf transcription in mature osteoblasts did not affect bone structure or bone mass in adulthood. However, Ngf knockout mice displayed significantly reduced periosteal bone accrual and osteogenic Wnt transcription in response to axial forelimb compression as compared to wildtype mice. Administration of a single dose of gambogic amide prior to the first of three bouts of axial forelimb compression significantly increased load-induced bone formation in wildtype mice, but failed to do so in either male or female Ngf knockout mice. Furthermore, increasing the frequency of gambogic amide administration to three daily doses resulted in a similar osteoanabolic effect without any adverse events. In total, our study reveals an important role for osteoblastic NGF in the skeletal adaptation of bone to mechanical forces, suggests that gambogic amide primarily functions in collaboration with endogenous NGF in bone, and provides insights for dose optimization of gambogic amide in future therapeutic applications.