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      Role of the Peripheral Nervous System in Skeletal Development and Regeneration: Controversies and Clinical Implications


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          Purpose of Review

          This review examines the diverse functional relationships that exist between the peripheral nervous system (PNS) and bone, including key advances over the past century that inform our efforts to translate these discoveries for skeletal repair.

          Recent Findings

          The innervation of the bone during development, homeostasis, and regeneration is highly patterned. Consistent with this, there have been nearly 100 studies over the past century that have used denervation approaches to isolate the effects of the different branches of the PNS on the bone. Overall, a common theme of balance emerges whereby an orchestration of both local and systemic neural functions must align to promote optimal skeletal repair while limiting negative consequences such as pain.


          An improved understanding of the functional bidirectional pathways linking the PNS and bone has important implications for skeletal development and regeneration. Clinical advances over the next century will necessitate a rigorous identification of the mechanisms underlying these effects that is cautious not to oversimplify the in vivo condition in diverse states of health and disease.

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          Most cited references130

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          Molecular Architecture of the Mouse Nervous System

          Summary The mammalian nervous system executes complex behaviors controlled by specialized, precisely positioned, and interacting cell types. Here, we used RNA sequencing of half a million single cells to create a detailed census of cell types in the mouse nervous system. We mapped cell types spatially and derived a hierarchical, data-driven taxonomy. Neurons were the most diverse and were grouped by developmental anatomical units and by the expression of neurotransmitters and neuropeptides. Neuronal diversity was driven by genes encoding cell identity, synaptic connectivity, neurotransmission, and membrane conductance. We discovered seven distinct, regionally restricted astrocyte types that obeyed developmental boundaries and correlated with the spatial distribution of key glutamate and glycine neurotransmitters. In contrast, oligodendrocytes showed a loss of regional identity followed by a secondary diversification. The resource presented here lays a solid foundation for understanding the molecular architecture of the mammalian nervous system and enables genetic manipulation of specific cell types.
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            Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.

            The primary sensory system requires the integrated function of multiple cell types, although its full complexity remains unclear. We used comprehensive transcriptome analysis of 622 single mouse neurons to classify them in an unbiased manner, independent of any a priori knowledge of sensory subtypes. Our results reveal eleven types: three distinct low-threshold mechanoreceptive neurons, two proprioceptive, and six principal types of thermosensitive, itch sensitive, type C low-threshold mechanosensitive and nociceptive neurons with markedly different molecular and operational properties. Confirming previously anticipated major neuronal types, our results also classify and provide markers for new, functionally distinct subtypes. For example, our results suggest that itching during inflammatory skin diseases such as atopic dermatitis is linked to a distinct itch-generating type. We demonstrate single-cell RNA-seq as an effective strategy for dissecting sensory responsive cells into distinct neuronal types. The resulting catalog illustrates the diversity of sensory types and the cellular complexity underlying somatic sensation.
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              Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats.

              Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.

                Author and article information

                Curr Osteoporos Rep
                Curr Osteoporos Rep
                Current Osteoporosis Reports
                Springer US (New York )
                14 August 2023
                14 August 2023
                : 21
                : 5
                : 503-518
                [1 ]Department of Medicine, Division of Bone and Mineral Diseases, Washington University, ( https://ror.org/00cvxb145) 660 South Euclid Avenue, Campus Box 8301, St. Louis, MO 63110 USA
                [2 ]Department of Biomedical Engineering, Johns Hopkins University, ( https://ror.org/00za53h95) Baltimore, MD USA
                [3 ]Translational Tissue Engineering Center, Johns Hopkins University, ( https://ror.org/00za53h95) Baltimore, MD USA
                [4 ]Department of Chemical and Biomolecular Engineering, Johns Hopkins University, ( https://ror.org/00za53h95) Baltimore, MD USA
                [5 ]Department of Materials Science and Engineering, Johns Hopkins University, ( https://ror.org/00za53h95) Baltimore, MD USA
                [6 ]Institute for Nanobiotechnology, Johns Hopkins University, ( https://ror.org/00za53h95) Baltimore, MD USA
                [7 ]Department of Biomedical Engineering, Washington University, ( https://ror.org/00cvxb145) MO St. Louis, USA
                [8 ]Department of Cell Biology and Physiology, Washington University, ( https://ror.org/00cvxb145) MO St. Louis, USA
                Author information
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                : 25 July 2023
                Funded by: Rita Levi-Montalcini Postdoctoral Fellowship
                Funded by: NSF-GRFP
                Funded by: FundRef http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;
                Award ID: T32-AR060719
                Award ID: P30-AR074992
                Award ID: R56-AR081251
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: R01-DK132073
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000072, National Institute of Dental and Craniofacial Research;
                Award ID: R01-DE027957
                Award Recipient :
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                © Springer Science+Business Media, LLC, part of Springer Nature 2023

                bone regeneration,peripheral nerve,ngf/trka,skeletal development,denervation,fracture healing


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