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.

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

“…These results were in line with in vivo evidence and could suggest that the absence of DPP3 altered the crosstalk between the OC and the OB lineage: on one hand, it increased Dpp3 KO OC precursors’ responsiveness to OB‐derived molecular cues; on the other, it reduced OB activity. Therefore, we evaluated the expression of coupling factors, namely RANKL, OPG, Ephb4 , Wnt5a , and Lrp5 for the OB side, Bmp6 , Efnb2 , Wnt10b , Sema4d , and Ror2 for the OC side . We found that KO OC/KO OB, KO OC/WT OB, and WT OC/WT OB co‐cultures produced a similar amount of RANKL, which was higher than that in WT OC/KO OB co‐cultures (Fig.…”

YAP1 inhibits the induction of TNF‐α‐stimulated bone‐resorbing mediators by suppressing the NF‐κB signaling pathway in MC3T3‐E1 cells

“…Osteoblasts are responsible for bone matrix secretion and mineralization, and they tightly regulate osteoclast activation and differentiation (Nakamichi et al, ). During bone resorption induced by inflammation, the receptor activator of nuclear factor‐κB ligand (RANKL), which is from osteoblasts and marrow‐derived stromal cells, promotes osteoclastic precursors differentiate into mature osteoclasts by binding to its cognate receptor, RANK (Han, You, Xing, Zhang, & Zou, ; Horowitz, Xi, Wilson, & Kacena, ; Steeve, Marc, Sandrine, Dominique, & Yannick, ). Osteoprotegerin (OPG), largely secreted by osteoblast lineage cells, functions as a soluble decoy receptor for RANKL that inhibits the RANKL/RANK link and osteoclastogenesis (Simonet et al, ).…”

Three‐dimensional intravital imaging in bone research

“…Bone remodeling is a constant process necessary to maintain the integrity and biological functions of the skeleton. Essentially, bone remodeling involves removal of old or damaged bone by osteoclasts and subsequent new bone formation by osteoblasts . Furthermore, osteocytes embedded in the bone matrix, as the terminally differentiated phenotype of osteoblasts, are previously thought to be less significant in bone remodeling, but recently emerged as a regulator of bone homeostasis .…”

“…As for cell‐cell interactions, previous studies have revealed both paracrine and endocrine actions of osteoblasts and osteoclasts to influence each other . However, evidence of direct cell‐cell contact between osteoclasts and osteoblasts is rarely provided, since they occupy discrete territories in the steady state.…”