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Review
doi: 10.1038/s41413-018-0019-6. eCollection 2018.

Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts

Affiliations
Review

Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts

Yujiao Han et al. Bone Res..

Abstract

The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes, and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin (SOST) that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influenceaA osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or "osteokines" from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin (OCN) secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2 (LCN2) is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain. We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Paracrine actions of osteoblasts, osteocytes, and osteoclasts-derived factors. Molecules secreted by osteoblasts, osteocytes, and osteoclasts influence each other in a paracrine manner to maintain the balance of bone formation and bone resorption. Osteoblasts activate osteoclast formation by expressing M-CSF, RANKL, and WNT5A and inhibit osteoclast activity through OPG, a decoy receptor of RANKL, SEMA3A, and WNT16. Osteocyte-derived SOST inhibits osteoblast differentiation and stimulates osteoclastogenesis. Osteoclasts also secrete coupling factors such as BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 to act on osteoblasts and osteocytes and thereby influence bone formation.
Fig. 2
Fig. 2
Regulation of angiogenesis by secretory factors from different bone cells. Bone formation and bone resorption are coupled by the process of angiogenesis. Pre-osteoblasts and chondrocytes-derived vascular endothelial growth factor A (VEGFA) can promote proliferation, survival and migration of endothelial cells (ECs), which express VEGF receptor 2 (VEGFR2). Hypoxia-inducible factor 1-α (HIF1α) can induce VEGFA expression in chondrocytes and pre-osteoblasts. Matrix metalloproteases (MMPs) can affect VEGF release from the ECM. Pre-osteoclast-secreted platelet-derived growth factor-BB (PDGF-BB) can induce Type H vessel formation and thereby stimulate bone formation.
Fig. 3
Fig. 3
Bone-derived FGF23 regulates phosphate metabolism. FGF23, synthesized by osteoblasts and osteocytes, inhibits phosphate resorption and suppresses the production of 1,25(OH)2D3 through its binding to a complex of FGFR1 and the co-receptor Klotho in the kidney. FGF23 also suppresses PTH synthesis and secretion in a Klotho-dependent fashion in the parathyroid. Synthesis and secretion of FGF23 by osteoblasts and osteocytes are positively regulated by 1,25(OH)2D3 and PTH. PTH derived from parathyroid can downregulate phosphate resorption and 1,25(OH)2D3 production in the kidney.
Fig. 4
Fig. 4
OCN is a bone-derived multifunctional hormone. OCN is C-carboxylated (GlaOCN) and secreted by osteoblasts into bone extracellular matrix (ECM). The acidic pH (~4.5) in the resorption lacunae formed by osteoclasts decarboxylates GlaOCN into undercarboxylated active osteocalcin (GluOCN), which enters the circulation to act as a hormone. GluOCN regulates energy metabolism via enhancement of glucose uptake in muscle, insulin production in the pancreas, insulin sensitivity in the liver and adipose tissue, upregulation of adiponectin expression in adipose tissue and promotion of β-cell proliferation in the pancreas. In addition, OCN promotes male fertility by stimulation of testosterone synthesis in Leydig cells which improves cognitive function of the brain through an increase in neurotransmitter synthesis and facilitation of hippocampus development. Notably, OCN functions in testis, pancreas and muscle through its binding to the receptor GPRC6A while receptor(s) of OCN in the brain, adipose, and liver still require identification.
Fig. 5
Fig. 5
Osteoblast-derived LCN2 suppresses food intake. LCN2 is secreted by osteoblasts and crosses the blood–brain barrier to accumulate in the hypothalamus, where it binds to its receptor MC4R in the hypothalamic neurons of the paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH) and activates MC4R-dependent anorexigenic signaling. In addition, LCN2 also directly regulates glucose tolerance, insulin sensitivity and insulin secretion.
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