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School of Medicine
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Roll of Sensory Nerves in Bone
Sensory nerves in the developing mouse embryo
Anyone who has broken a bone is aware of the existence and function of sensory nerves in bone. However, little is known about how nerves innervate the skeleton and what purpose beyond pain these nerves perform.
In this project, we will use several 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. Our results are expected to yield new insights into their role.
- NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Reports, 2016; 16:2723-35. PMID: 27568565
- 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. Proc Natl Acad Sci U S A, 2017 May 2; 114(18):E3632-E3641
Bone and Energy Metabolism
Proposed bone pancreas endocrine loop
Our recent studies suggest the existence of a novel endocrine regulatory loop through which insulin signaling in the osteoblast participates in the regulation of global energy metabolism. This 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.
- Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere M-C, Hussain MA, Bru?ning J and Clemens, TL. Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell, 2010; 142:309-19
- Riddle RC, Frey JL, Tomlinson RE, Ferron M, Li Y, DiGirolamo DJ, Faugere MC, Hussain MA, Karsenty G, Clemens TL. Tsc2 is a molecular checkpoint controlling osteoblast development and glucose homeostasis. Mol Cell Biol., 2014; 34:1850-62
- Frey JL, Li Z, Ellis JM, Zhang Q, Farber CR, Aja S, Wolfgang MJ, Clemens TL, Riddle RC. Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Mol Cell Biol., 2015. 1343-14
- Li Z, Frey JL, Wong GW, Faugere MC, Wolfgang MJ, Kim JK, Riddle RC, Clemens TL. Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in Osteoblasts. Endocrinology, 2016; 157:4094-4103
Bone as Central to Metabolism by Thomas Clemens
The endochondral skeleton evolved over 300 million years ago when the first animals colonized land. Survival of terrestrial vertebrates in this new environment required wholesale adaptations in their anatomy and physiology. A larger musculoskeletal system enabled ambulation against increased gravitational forces and new strategies evolved to regulate extracellular mineral ion levels. The upgraded musculoskeletal system provided a storage site for scarce minerals essential for life, but also increased overall fuel requirements and altered global energy balance, prompting the evolution of endocrine networks to coordinate energy expenditure.