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

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.

Bone Metabolism: Functions of secretory proteins from bone cells

Proteins secreted from bone cells (osteoblasts, osteocytes, and osteoclasts) regulate the formation of osteoblasts, osteoclasts, and new blood vessels in a paracrine (local hormonal action) manner. The human skeleton is constantly being modeled, and that remodeling involves the removal of old or damaged bone by osteoclasts and its subsequent replacement with new bone by osteoblasts. Osteocytes inhibit osteoblast differentiation and promote osteoclast differentiation. A team headed by Weiguo Zou of the Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, reviewed recent progress that has been made regarding the hormonal functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. The authors highlight the growing awareness of how bone functions as both a paracrine and endocrine (distant hormonal action) organ, which is of great importance in developing treatments for metabolic disorders and degenerative diseases.