Neural Regulation of Bone and Bone Marrow

Abstract

Bones provide both skeletal scaffolding and space for hematopoiesis in its marrow. Previous work has shown that these functions were tightly regulated by the nervous system. The central and peripheral nervous systems tightly regulate compact bone remodeling, its metabolism, and hematopoietic homeostasis in the bone marrow (BM). Accumulating evidence indicates that the nervous system, which fine-tunes inflammatory responses and alterations in neural functions, may regulate autoimmune diseases. Neural signals also influence the progression of hematological malignancies such as acute and chronic myeloid leukemias. Here, we review the interplay of the nervous system with bone, BM, and immunity, and discuss future challenges to target hematological diseases through modulation of activity of the nervous system.

Figure 1.

Schematic illustration depicting the anatomic origin of sympathetic, parasympathetic, and sensory innervation of bone. PNS, Parasympathetic nervous system.

Figure 2.

Schematic illustration summarizing central nervous system (CNS) regulators of bone remodeling.

Figure 3.

Autonomic signals modulate hematopoietic stem cell (HSC) niche homeostasis at steady state. Peripheral sympathetic neurons are one of the main components of a healthy HSC niche. Circadian noradrenaline secretion from sympathetic nerve terminals leads to circadian expression of C-X-C chemokine ligand 12 (CXCL12) by Nestin^high/NG2⁺ perivascular mesenchymal stem cells (MSCs), resulting in rhythmic release of HSCs to the periphery. The adrenergic signals in this case are mediated through the β3-adrenergic receptor (AR). Secretion of HSC maintenance factors such as stem cell factor (SCF) and CXCL12 by Nestin^high/NG2⁺ MSCs keeps a subset of HSCs quiescent and in close association with arteriolar blood vessels, ensheathed with sympathetic nervous system (SNS) nerve fibers. When activated, HSCs relocate near the Nestin^low leptin receptor (LepR)-expressing perisinusoidal area. SNS signals also regulate bone formation via β2-AR signaling in osteoblasts. In addition to SNS nerves, nonmyelinating Schwann cells also maintain HSC dormancy through activation of the transforming growth factor β (TGF-β)/SMAD signaling.

Figure 4.

Altered hematopoietic stem cell (HSC) niche, including sympathetic neuropathy, promotes progression of hematological malignancies. (A) In a mouse model of chronic myelogenous leukemia (CML), BCR-ABL⁺ leukemic cells produce cytokines, including C-C motif ligand 3 (CCL3) and thrombopoietin (TPO), and mesenchymal stem cells (MSCs) show skewed differentiation toward osteolineage cells. HSC maintenance factors such as SCF and CXCL12 are down-regulated in these remodeled MSCs, leading to impaired hematopoiesis. Imatinib treatment partially corrects the alteration of HSC maintenance factor expression in MSCs. (B) In an acute myelogenous leukemia (AML) mouse model transduced with mixed lineage leukemia AF9 (MLL-AF9) retrovirus, catecholaminergic fibers around arterioles are degenerated. Neuropathy is accompanied by expanded β2-adrenergic receptor (AR)-expressing MSCs that are directed toward the osteoblastic cells. Similar to the CML mouse model, the expression of HSC maintenance factors is decreased in MSCs and normal hematopoiesis is compromised. (C) In a myeloproliferative neoplasm (MPN) mouse model harboring human Janus kinase 2 (JAK2[V617F]) transgene, mutant hematopoietic stem and progenitor cells (HSPCs) secrete interleukin 1β (IL-1β) that damages sympathetic nervous system (SNS) fibers and Schwann cells. In contrast to AML mice, neuropathy results in apoptosis of β3-AR-expressing MSCs and a reduction of these cells.

Figure 5.

The nervous system fine-tunes the inflammatory responses and maintains the immune homeostasis. (A) Sensory nerves are activated by inflammatory signals, leading to the secretion of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) from nerve endings. These substances induce proinflammatory responses through several processes, including enhancing blood flow and trafficking leukocytes to inflammation sites. Activated sensory nerves also transmit pain information to the central nervous system (CNS). On the other hand, sensory nerves can evoke anti-inflammatory responses through dopamine production in the adrenal glands. (B) Activation of hypothalamic–pituitary–adrenal (HPA) axis by inflammatory mediators leads to the glucocorticoid secretion from the adrenal cortex. This hormone prevents trafficking of immune cells from immune organs to inflammation sites, acting as an anti-inflammatory mechanism. (C) The sympathetic nervous system (SNS) is proinflammatory in the early stage of inflammation, which might be attributable in part to the fact that norepinephrine (NE) promotes inflammation through α-adrenergic receptors (ARs) at low concentrations. In contrast, high concentrations of NE suppress inflammation through β-ARs, which could underlie the observation that adrenergic signals have an anti-inflammatory impact at the later stage of inflammation. (D) Afferent branches of the parasympathetic nervous system (PNS) are activated by cytokines, including interleukin (IL)-1β from inflammation sites and signals are sent to the nucleus tractus solitarius (the parasympathetic brain region). This, in turn, activates efferent branches of the PNS, referred to as “inflammatory reflex.” Signals through the nAChRα7 subunit of macrophages inhibit the production of proinflammatory cytokines such as tumor necrosis factor (TNF) in these cells, rendering the PNS an anti-inflammatory mechanism. The origin of acetylcholine (ACh) that acts on macrophages is controversial and among the candidates are the efferent branches of the PNS and immune cells, including CD4⁺ T cells and macrophages that are triggered by NE from the SNS.