Table 1 Factors involved in skeletal interoception

Neurotransmitters and Neuropeptides

NE

Synthesis and secretion NE: secreted by sympathetic adrenergic nerves⁷⁶

Regulation (1) enzymes MAOa and MAOp: expressed in osteoblast precursor cells and in fully differentiated osteoblasts^77,78 (2) NE transporter: expressed in differentiated osteoblasts⁷⁷

ACh

Synthesis and secretion ACh: secreted by cholinergic nerves⁷⁹

Regulation (1) VAChT, the choline transporter, and CarAT: expressed in osteoblasts^80,81 (2) AChE and BChE: expressed in osteoblasts^80,81

CGRP

Synthesis and secretion CGRP: secreted by sensory nerves⁸²

Regulation CGRP: expressed in human osteosarcoma cells and primary osteoblasts⁸³

VIP

Synthesis and secretion VIP: secreted by cholinergic nerves^84,85

Regulation VIP: expressed in isolated pure populations of osteoclasts⁸⁶

NPY

Synthesis and secretion NPY: secreted by sympathetic adrenergic nerves⁸⁷

Regulation NPY: produced by osteocytes and osteoblasts⁸⁸

SP

Synthesis and secretion SP: secreted by sensory nerves^89,90

Regulation SP and the receptor NK-1: expressed in osteoblasts and osteocytes especially under mechanical stimulation during exercise⁹¹

Axon guidance factors

Sema3A

Synthesis and secretion Sema3A: secreted by a specific subset of nerves including sensory nerves⁹²

Synthesis and secretion Sema3A: secreted by osteoblast lineage cells and expressed in bone cell lineages including chondrocytes, osteoblasts, and osteoclasts^93,94

Sema4D

Synthesis and secretion Sema4D and its receptors plexin-B1, plexin-B2: expressed in embryonic dorsal root ganglion⁹⁵

Synthesis and secretion Sema4D: strongly expressed in osteoclasts, with no evidence of its expression in osteoblasts^96,97,98,99

Netrin-1

Synthesis and secretion Netrin-1: continuously expressed in the nervous system. Expression in SCs upregulated during nerve repair¹⁰⁰

Synthesis and secretion Netrin-1: produced by osteoblasts and osteoclast. Expression of Netrin-1 in osteoblasts was found to be 200-fold higher than that in osteoclasts^101,102,103

Slit-3

Synthesis and secretion Slit-3: expressed in the cell bodies and axons of both motor and sensory neurons, satellite cells of the dorsal root ganglion, SCs and fibroblasts of peripheral nerves¹⁰⁴

Synthesis and secretion Slit-3: secreted by osteoclasts and osteoblasts. Production increasing during osteoclast differentiation^105,106

Neurotrophins

NGF

Synthesis and secretion NGF: highly concentrated in the nervous system during nerve development or regeneration. Secreted by SCs of peripheral nerves¹⁰⁷

Synthesis and secretion NGF: expressed in bone marrow stromal cells, osteoblasts as well as osteoblastic cell lines. Expression of NGF is upregulated during proliferation or upon loading^108,109,110

BDNF

Synthesis and secretion BDNF: highly concentrated in the nervous system during nerve development or regeneration. Secreted by SCs of peripheral nerves¹⁰⁷

Synthesis and secretion BDNF and its receptor TrkB: expressed in fracture bone tissues during early bone formation. Concentrated in endothelial and osteoblastic cells^108,111,112