TABLE 1.

Osteocytes and the activation phase of bone remodeling.

Origin of osteocytes	Differentiation stages: (i) From mature osteoblasts to preosteocyte type I with dendritic projections formation; (ii) from preosteocyte type I to preosteocyte type II with cytoskeleton rearrangement; (iii) from preosteocyte type II to preosteocyte type III (mature osteocyte trapped within the mineralized bone matrix) with canaliculae formation (Hirao et al., 2007; Paiva and Granjeiro, 2017).
Important factors involved in osteocytogenesis	(i) Pre-osteoblasts (Stro1, CD29, CD105, CD166); (ii) Osteoblast (Cbfa1 and osterix for differentiation, alkaline phosphase and collagen for the production of osteoid, osteocalcin, casein kinase II); (iii) Osteoid osteocyte (Phex and MEPE for regulation of biomineralization and mineral metabolism, E11/gp38 and MMP-14 for dendrite/canaliculi formation, destrin for cytoskeleton rearrangement); (iv) Mineralizing osteocyte (DMP1 for regulation of biomineralization and mineral metabolism, CapG for cytoskeleton regulation); (v) Mature osteocyte (sclerostin, FGF23 for regulation of renal phosphate excretion, ORP150 for preserving viability in a hypoxic environment) (Bonewald, 2011). Other factors include TGF-β (D’Angelo et al., 2001; Karsdal et al., 2002), MMP-2/MMP-13/MMP-14 proteolytic axis (Barthelemi et al., 2012), Cx43, Dkk-1, Fetuin A, RANKL, MCS-F, and osteoprotegerin (Chen et al., 2018).
Key signaling events involved in osteocytogenesis	Osteocalcin, ALP, and other genes specific for osteoblast differentiation gradually downregulate (Paiva and Granjeiro, 2017). At the same time, different genes specific for osteocyte differentiation upregulate (such as CD44 [Hughes et al., 1994], E11/gp38 [Zhang et al., 2006], Phex [Ruchon et al., 2000; Westbroek et al., 2002], Fimbrin [Tanaka-Kamioka et al., 1998], MEPE [Rowe et al., 2004], DMP1 [Feng et al., 2006; Toyosawa et al., 2012], sclerostin [Poole et al., 2005; Balemans et al., 2008], ORP150 [Gao et al., 2010], and FGF23 [Liu et al., 2006]). Transcription factors involved in the process of osteoblast/osteocyte transition are ATF-4, whose expression is regulated by JNK, and members of the AP-1 group (Matsuguchi et al., 2009).
Role of osteocytes	(i) Maintain physical connections with each other, and also other players (osteoclasts, osteoblasts) of the bone remodeling cycle through a widespread network of tiny channels called canaliculi (Civitelli, 2008). (ii) May remodel the perilacunar matrix (e.g., during lactation) by expressing cathepsin K and acid phosphatase. (iii) Regulate bone remodeling by expressing M-CSF and RANKL (stimulate osteoclast formation and activity) as well as NO and OPG (inhibit osteoclast formation and activity). Also, osteocytes control bone formation by secreting activators (e.g., NO, ATP, PEG2) and inhibitors (e.g., sFRP1, DKK1, sclerostin) of the Wnt signaling pathway. (iv) Source of factors (e.g., sclerostin) and regulators (e.g., FGF-23, DMP-1, Phex, MEPE) of phosphate metabolism. (v) Manage the bone’s reservoir of calcium. (vi) Function as mechanosensory cells (Bonewald, 2011; Dallas et al., 2013; Bellido, 2014).
Molecular mechanism that underlies the function of osteocytes as mechanosensory cells	Osteocytes are good mechanosensors (i.e., they detect changes of mechanical stimuli) in bone tissue which serve to sense and respond to alterations produced when a bone is mechanically loaded. Such alterations may be physical deformation of the bone matrix, fluid flow shear stress generated by variations in canalicular fluid flow and electrical streaming potentials (Bonewald and Mundy, 1990; Mundy, 1993; Manolagas, 2000; Miyauchi et al., 2000; Bonewald and Johnson, 2008; Datta et al., 2008; Parra-Torres et al., 2013; Takemura et al., 2019). Mechanical strain signal is converted into a cellular response (i.e., biochemical signals) with the participation of membrane proteins (such as CD44, connexins, integrins, and ion channels) and downstream mediators of intracellular signaling (such as guanine regulatory proteins, mitogen activated protein kinase, cyclic adenosine monophosphate, inositol triphosphate, and intracellular calcium) (Rawlinson et al., 1996; Burger and Klein-Nulend, 1999; Mikuni-Takagaki, 1999; Miyauchi et al., 2000; Gu et al., 2001; Alford et al., 2003; Kapur et al., 2003; Plotkin et al., 2005; Rubin et al., 2006; Miyauchi et al., 2006). On the other hand, bone remodeling is also controlled by upregulation of RANKL and sclerostin in response to a decrease in mechanical signals (Parra-Torres et al., 2013). The precise signaling biochemical pathways (e.g., Wnt/β-catenin) and regulatory mechanisms that may mediate adaptive responses activated by mechanical loading and unloading in bone remain to be completely delineated (Dallas et al., 2013; Parra-Torres et al., 2013).
Other consequences of osteocyte activities on bone remodeling	Retraction of the bone lining cells (elongated mature osteoblasts) on the endosteal surface (which is a thin layer of cell-rich connective tissue), and also digestion of the underlying collagenous membrane by collagenases (Murray et al., 1995; Karsdal et al., 2001; Datta et al., 2008; Kerschan-Schindl and Ebenbichler, 2012).

MMP, matrix metalloproteinase; TGF, transforming growth factor; RANKL, receptor activator of nuclear factor kappa B ligand; MAPK, mitogen-activated protein kinase; TIMP, tissue inhibitor of metalloproteinase; ALP, alkaline phosphatase; Phex, phosphate-regulating endopeptidase homolog X-linked; MEPE, matrix extracellular phosphoglycoprotein; Cx, connexin; Dkk, Dickkopf WNT signaling pathway inhibitor; Phex, phosphate-regulating endopeptidase homolog X-linked; DMP, dentin matrix acidic phosphoprotein precursor; M-CSF, Macrophage colony-stimulating factor; ORP, oxygen regulated protein; FGF, fibroblast growth factor; ATF, activating transcription factor; JNK, c-Jun N-terminal kinase; AP, activator protein; CD29, integrin beta-1; CD105, endoglin; CD166, activated leukocyte cell adhesion molecule; CapG, capping actin protein, gelsolin like; ORP150, 150-kDa oxygen-regulated protein; OPG; osteoprotegerin, ATP, adenosine triphosphate; NO, nitric oxide; sFRP1, secreted frizzled-related protein 1; DKK1, Dickkopf WNT signaling pathway inhibitor 1; PEG2, prostaglandin E2; Wnt, Wingless-type MMTV integration site family.