Crosstalk between Bone and Nerves within Bone

Abstract

For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve-resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress-related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.

Keywords: bioactive factors; bone metabolism; crosstalk; nerve growth; peripheral nerves.

Figure 1

Crosstalk between bone and peripheral nerves within the skeleton. NE: norepinephrine; ACh: acetylcholine; NPY: neuropeptide Y; VIP: vasoactive intestinal peptide; SP: substance P; CGRP: calcitonin gene‐related peptide; BMSCs: bone marrow derived stroma cells. [Adopted from SMART Servier Medical ART under the terms of the CC‐BY Creative Commons Attribution 3.0 Unported license. (http://creativecommons.org/licenses/by/3.0/).]

Figure 2

Participation of cells from nerves in embryonic bone development and bone regeneration. A) Nerve‐resident mesenchymal cells contribute to bone regeneration. B) Pdgfra‐positive mesenchymal cells can adopt features of bone and cartilage lineage cells when differentiated in vitro. C) Many TdT‐positive, Pdgfra‐EGFP‐positive, p75‐negative nerve‐derived mesenchymal cells are found located within and immediately adjacent to the regenerating bone. D) Mouse skeletal stem cells rely on paracrine factors secreted by Schwann cells as the underlying mechanism for mandibular bone regeneration. E) Schwann cell precursors generate osteoprogenitor cells and osteocytes in facial region and trunk during murine embryonic development. Schwann cell precursors progeny in Plp1CreERT2; R26RYFP/+ embryos traced from E11.5 to E17.5 were positive for osteoprogenitor marker OSX in the ossified parts of mandible, rib, and scapula. (A–C) Reproduced with permission.^{[ 134 ]} Copyright 2018, Elsevier. (D) Reproduced under the terms of a Creative Commons Attribution license (CC‐BY‐4.0).^{[ 136 ]} Copyright 2019, The Authors. Published by Elsevier. (E) Reproduced with permission.^{[ 135 ]} Copyright 2019, The Authors. Published by National Academy of Sciences.

Figure 3

A) The communication between bone and intrabony nerves is like Dominoes. B) In response to stimulation from environment, bone lineage cells can release signals to function on nerves within bone. Consequently, the affected nerves may send out signals to regulate the bioactivities of the bone.

Figure 4

Metabolism of neurotransmitters. The images illustrate the synthesis, reuptake and catabolism of neurotransmitters. NE: norepinephrine. ACh: acetylcholine. TH: tyrosine hydroxylase. l‐DOPA: dihydroxyphenylalanine. DA: dopamine. LAAD: l‐aromatic amino acid decarboxylase. DBH: dopamine β‐hydroxylase. NET: NE transporter. MAO: monoamine oxidase. COMT: catechol‐O‐methyltransferase. ChAT: choline acetyltransferase. VAChT: vesicular ACh transporter. AChE: acetylcholine esterase. BChE: butyrylcholinesterases. CarAT: carnitine acetyl transferase.

Figure 5

A) Possible crosstalk between bone and peripheral nerves in patients with psychological stress, Alzheimer's disease, osteoporosis, and impaired bone repair and endochondral ossification. B) Possible crosstalk between bone and peripheral nerves within the skeleton in patients with bone‐related tumor. NE: norepinephrine.

Figure 6

Crosstalk between bone and peripheral nerves within the skeleton during osteoarthritis. A) Innervation of cartilage, subchondral bone, synovium and the joint capsule during osteoarthritis. Blue indicates sensory nerves. Yellow indicates sympathetic nerves. B) Regulatory roles of sympathetic nerves on bone metabolism during osteoarthritis. NE released by sympathetic nerves play a regulatory role on bone metabolism during TMJ osteoarthritis caused by unilateral anterior crossbite through acting on β2AR (Adrb2). And selective deletion of β2AR (Adrb2) in nestin⁺ MSCs could attenuate progression of condylar subchondral bone loss as well as cartilage degradation. C: Bilateral communication between bone and peripheral sensory nerves during OA. SNS: sympathetic nerve system. NE: norepinephrine. Adrb2: β2‐adrenergic receptors. NGF: nerve growth factor. SP: substance P. CGRP: calcitonin gene‐related peptide. BMSC: bone marrow derived stroma cell.

Figure 7

Crosstalk between bone and peripheral nerves within the skeleton during heterotrophic ossification (HO). Neuropeptides and neurotransmitters from peripheral nerves regulate BAT production and mast cell degranulation. Cells derived from peripheral nerves are transported to the HO site and function as osteoprogenitors. BMP2 from the bone matrix triggers the release of neuropeptides by peripheral nerves as well as increases the permeability of blood‐nerve barrier for cells and other biological factors. NE: norepinephrine. SP: substance P. CGRP: calcitonin gene‐related peptide. BAT: brown adipose tissue. BMP2: bone morphogenetic protein 2. [Some drawing elements are adopted from SMART Servier Medical ART under the terms of the CC‐BY Creative Commons Attribution 3.0 Unported license. (http://creativecommons.org/licenses/by/3.0/).] Adapted with permission,^{[ 299 ]} copyright 2018, Frontiers Media S.A.

Figure 8

Future perspectives on targeting the crosstalk between bone and peripheral nerves for disease treatment or tissue regeneration. A) Schematic showing the future perspectives. B) Targeting peripheral nerves within bone may promote bone fracture healing. Blue dotted frames indicate the potential target. C) Schematic showing simultaneous regeneration of bone and nerves using implanted scaffolds. (B) Reproduced with permission.^{[ 336 ]} Copyright 2020, Elsevier.