The skeleton is one of the most important structures in our bodies. Bones allow us to stand, walk and move from one place to another, and they serve as protectors of our vital organs. Degradation of our bones structure ? osteoporosis ? is a global health problem. The long-term goal of my research is to understand the cellular and molecular mechanisms governing skeletal development, homeostasis and repair. Currently, we are studying the coupling of bone cell metabolic activity the role of sensory nerves in bone development and function. Studies supported by my Merit Review Award identified a novel pathway that links the metabolic activity of skeletal osteoblasts to global fuel metabolism and energy expenditure. Insulin receptor signaling in the osteoblast regulates the production and bioavailability of osteocalcin, which in turn, acts in an endocrine fashion to regulate pancreatic insulin secretion and peripheral insulin responsiveness. The existence of this bone-panaceas endocrine loop suggests that bone consumes a significant proportion of the body?s overall fuel supply, and consequently is in competition with other energy consuming tissues. Currently, we are studying mouse models with genetic alterations that selectively attenuate either glucose or fatty acid metabolism. These models will be used to determine the fuel requirements of bone accrual and determine the impact of energy substrate oxidation and metabolism by osteoblasts on global energy flux during post-natal bone development and in response to discrete anabolic episodes. The importance of these metabolic pathways humans is profoundly illustrated by metabolic diseases such as diabetes and osteoporosis caused by genetic or environmental disturbances in endocrine control mechanisms. In another project sponsored by NIH we are investigating the role of sensory nerves on bone development and repair. Developing tissues dictate the amount and type of innervation they require by secreting neurotrophins, which promote neuronal survival by activating distinct tyrosine kinase receptors. We show that nerve growth factor (NGF) signaling through neurotrophic tyrosine kinase receptor type 1 (TrkA) directs innervation of the developing mouse femur to promote vascularization and osteoprogenitor lineage progression. At the start of primary ossification, TrkA-positive axons penetrate perichondrial bone surfaces, coincident with NGF expression in cells adjacent to centers of incipient ossification. Inactivation of TrkA signaling during embryogenesis in TrkA(F592A) mice impaired innervation, delayed vascular invasion of the primary and secondary ossification centers, decreased numbers of Osx-expressing osteoprogenitors, and decreased femoral length and volume. These same phenotypic abnormalities were observed in mice following tamoxifen-induced disruption of NGF in Col2-expressing perichondrial osteochondral progenitors. These findings indicate that NGF serves as a skeletal neurotrophin to promote sensory innervation of developing long bones, a process critical for normal primary and secondary ossification. Similarly, NGF-TrkA signaling played an important role during fracture repair in mice engineered with conditional TrkA alleles. NGF- enriched populations accumulated within the soft callus with progressive accumulation of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum, at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice over time of fracture significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed consolidation of the callus. Delayed response to fracture was also observed in mice following treatment with cisplatinum to induce neuropathy.
The long-term goal of my research is to understand the cellular and molecular mechanisms governing skeletal development, homeostasis and repair. One project examines fuel consumption by osteoblasts and osteocytes under normal conditions and in response to well-defined stimuli, which increase bone cell energy demands. Such information will help clarify how and why bone communicates with other energy consuming tissues, and may explain the close association between the existence of bone disease and diabetes in humans; which should have an immediate impact on the management, treatment and prevention of these related metabolic disturbances. In a second project, we are using novel approaches to characterize the timing of innervation, and the consequence of blocking nerve action on bone development and repair. These studies represent the first comprehensive approach to investigating the function of sensory nerves in bone.
