PMID- 29486004 OWN - NLM STAT- MEDLINE DCOM- 20180412 LR - 20230814 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 13 IP - 2 DP - 2018 TI - Temporal mechanically-induced signaling events in bone and dorsal root ganglion neurons after in vivo bone loading. PG - e0192760 LID - 10.1371/journal.pone.0192760 [doi] LID - e0192760 AB - Mechanical signals play an integral role in the regulation of bone mass and functional adaptation to bone loading. The osteocyte has long been considered the principle mechanosensory cell type in bone, although recent evidence suggests the sensory nervous system may play a role in mechanosensing. The specific signaling pathways responsible for functional adaptation of the skeleton through modeling and remodeling are not clearly defined. In vitro studies suggest involvement of intracellular signaling through mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and mammalian target of rapamycin (mTOR). However, anabolic signaling responses to bone loading using a whole animal in vivo model have not been studied in detail. Therefore, we examined mechanically-induced signaling events at five time points from 0 to 24 hours after loading using the rat in vivo ulna end-loading model. Western blot analysis of bone for MAPK's, PI3K/Akt, and mTOR signaling, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to estimate gene expression of calcitonin gene-related protein alpha (CGRP-alpha), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), c-jun, and c-fos in dorsal root ganglion (DRG) of the brachial intumescence were performed. There was a significant increase in signaling through MAPK's including extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) in loaded limbs at 15 minutes after mechanical loading. Ulna loading did not significantly influence expression of the genes of interest in DRG neurons. Bone signaling and DRG gene expression from the loaded and contralateral limbs was correlated (SR>0.40, P<0.05). However, bone signaling did not correlate with expression of the genes of interest in DRG neurons. These results suggest that signaling through the MAPK pathway may be involved in load-induced bone formation in vivo. Further characterization of the molecular events involved in regulation of bone adaptation is needed to understand the timing and impact of loading events, and the contribution of the neuronal signaling to functional adaptation of bone. FAU - Bleedorn, Jason A AU - Bleedorn JA AUID- ORCID: 0000-0003-2987-7722 AD - Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Hornberger, Troy A AU - Hornberger TA AD - Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Goodman, Craig A AU - Goodman CA AD - Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. AD - College of Health and Biomedicine, Victoria University, Melbourne, Victoria, Australia. AD - Australian Institute of Musculoskeletal Science (AIMSS), Victoria University, St Albans, Victoria, Australia. FAU - Hao, Zhengling AU - Hao Z AD - Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Sample, Susannah J AU - Sample SJ AD - Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Amene, Ermias AU - Amene E AD - Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Markel, Mark D AU - Markel MD AD - Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Behan, Mary AU - Behan M AD - Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. FAU - Muir, Peter AU - Muir P AD - Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. LA - eng GR - R01 AR057347/AR/NIAMS NIH HHS/United States GR - R56 AR057347/AR/NIAMS NIH HHS/United States GR - AR057347/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180227 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Bone and Bones/*metabolism MH - Ganglia, Spinal/cytology/*metabolism MH - Gene Expression MH - MAP Kinase Signaling System MH - Male MH - Neurons/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - *Signal Transduction MH - *Stress, Mechanical MH - TOR Serine-Threonine Kinases/metabolism MH - Ulna/metabolism/physiopathology PMC - PMC5828357 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2018/02/28 06:00 MHDA- 2018/04/13 06:00 PMCR- 2018/02/27 CRDT- 2018/02/28 06:00 PHST- 2017/11/16 00:00 [received] PHST- 2018/01/30 00:00 [accepted] PHST- 2018/02/28 06:00 [entrez] PHST- 2018/02/28 06:00 [pubmed] PHST- 2018/04/13 06:00 [medline] PHST- 2018/02/27 00:00 [pmc-release] AID - PONE-D-17-40605 [pii] AID - 10.1371/journal.pone.0192760 [doi] PST - epublish SO - PLoS One. 2018 Feb 27;13(2):e0192760. doi: 10.1371/journal.pone.0192760. eCollection 2018.