Journal of Functional Morphology and Kinesiology Review The Osteocyte: From “Prisoner” to “Orchestrator” Carla Palumbo * and Marzia Ferretti Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; [email protected] * Correspondence: [email protected] Abstract: Osteocytes are the most abundant bone cells, entrapped inside the mineralized bone matrix. They derive from osteoblasts through a complex series of morpho-functional modifications; such modifications not only concern the cell shape (from prismatic to dendritic) and location (along the vascular bone surfaces or enclosed inside the lacuno-canalicular cavities, respectively) but also their role in bone processes (secretion/mineralization of preosseous matrix and/or regulation of bone remodeling). Osteocytes are connected with each other by means of different types of junctions, among which the gap junctions enable osteocytes inside the matrix to act in a neuronal-like manner, as a functional syncytium together with the cells placed on the vascular bone surfaces (osteoblasts or bone lining cells), the stromal cells and the endothelial cells, i.e., the bone basic cellular system (BBCS). Within the BBCS, osteocytes can communicate in two ways: by means of volume transmission and wiring transmission, depending on the type of signals (metabolic or mechanical, respectively) received and/or to be forwarded. The capability of osteocytes in maintaining skeletal and mineral homeostasis is due to the fact that it acts as a mechano-sensor, able to transduce mechanical strains into biological signals and to trigger/modulate the bone remodeling, also because of the relevant role of sclerostin secreted by osteocytes, thus regulating different bone cell signaling pathways. The authors want to emphasize that the present review is centered on the morphological aspects of the osteocytes that clearly explain their functional implications and their role as bone orchestrators. Citation: Palumbo, C.; Ferretti, M. The Osteocyte: From “Prisoner” to Keywords: osteocytes; bone mechano-sensor; skeletal homeostasis; mineral homeostasis; bone “Orchestrator”. J. Funct. Morphol. remodeling Kinesiol. 2021, 6, 28. https://doi.org/ 10.3390/jfmk6010028 Academic Editor: Pietro Scicchitano 1. Osteoblast-to-Osteocyte Transformation It has been known for more than a century [1–3] that the osteocyte originates from the Received: 5 February 2021 osteoblast. However, the process of osteoblast-to-osteocyte differentiation has been widely Accepted: 11 March 2021 Published: 17 March 2021 investigated only at a later time point with regard to both morphological and functional aspects. The structural differences between osteoblasts and osteocytes were shown by vari- Publisher’s Note: MDPI stays neutral ous authors in the 1960s to1980s [4–8], but only afterwards was established the temporal with regard to jurisdictional claims in sequence of the events that allows the transformation of the prismatic osteoblast (generally published maps and institutional affil- arranged in laminae facing the vascular bone surfaces) into the dendritic mature osteocyte iations. (embedded in the mineralized matrix) [9–11]. Concerning the dynamic modification of the cell body of preosteocyte (i.e., the differentiating osteocyte), the amount of the cytoplasmic organelles decreases, whereas the nucleus-to-cytoplasm ratio increases depending on the diminution of its secretive activity [9]. In parallel to both the cellular body reduction in size and the modification in ultrastructure, the formation of the cytoplasmic processes proceeds Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. with an asynchronous and asymmetric pattern, considering that the cells in differentiation This article is an open access article are progressively further away from the vascular surface due to the osteoid secreted by distributed under the terms and the osteoblastic lamina (Figure1): firstly, the differentiating osteocytes maintain contacts conditions of the Creative Commons with the mature osteocytes that recruited them from the osteoblastic lamina, forming short Attribution (CC BY) license (https:// “mineral” processes; later, they establish contacts with the migrating osteoblastic lamina, creativecommons.org/licenses/by/ elongating slender and long “vascular” processes, issued before the complete mineraliza- 4.0/). tion of the surrounding osteoid. The asynchronous and asymmetrical dendrogenesis is the J. Funct. Morphol. Kinesiol. 2021, 6, 28. https://doi.org/10.3390/jfmk6010028 https://www.mdpi.com/journal/jfmk J. Funct. Morphol. Kinesiol. 2021, 6, x FOR PEER REVIEW 2 of 18 J. Funct. Morphol. Kinesiol. 2021, 6, 28 2 of 17 with the migrating osteoblastic lamina, elongating slender and long “vascular” processes, issued before the complete mineralization of the surrounding osteoid. The asynchronous and asymmetrical dendrogenesis is the expression of the fact that osteocytes (as all bone expressioncells) live in of an the asymmetrical fact that osteocytes environment, (as all bone between cells) live the in mature an asymmetrical mineralized environment, matrix and betweenthe vascular the maturesurface mineralized(covered by osteoblastic matrix and thelaminae vascular or bone surface lining (covered cells); thus, by osteoblastic it is logical laminaeto expect or that bone not lining only cells);the osteocytes, thus, it is but logical also to the expect preosteocytes that not only and thethe osteocytes,osteoblasts, but are alsomorpho the preosteocytes‐functionally asymmetric and the osteoblasts, cells. are morpho-functionally asymmetric cells. FigureFigure 1.1. Schematic drawing drawing showing showing the the asynchronous asynchronous and and asymmetric asymmetric pattern pattern of ofcytoplasmic cytoplasmic processes formation during osteocyte differentiation (preosteocytes = black; osteoblasts = white). processes formation during osteocyte differentiation (preosteocytes = black; osteoblasts = white). (A) Preosteocyte enlarges its secretory territory, thus reducing its appositional growth rate, and (A) Preosteocyte enlarges its secretory territory, thus reducing its appositional growth rate, and starts to radiate processes towards the osteoid. (B) Preosteocyte, located inside the osteoid seam startsbut still to in radiate contact processes with the towards osteoblastic the osteoid.lamina, continues (B) Preosteocyte, to radiate located short and inside thick the cytoplasmic osteoid seam butprocesses still in only contact from with its mineral the osteoblastic‐facing side. lamina, (C) Preosteocyte, continues to before radiate being short completely and thick cytoplasmicburied by processesminerals, radiates only from long its and mineral-facing slender processes side. ( Cfrom) Preosteocyte, its vascular‐ beforefacing beingside to completely remain in touch buried with by minerals,the osteoblastic radiates lamina. long and slender processes from its vascular-facing side to remain in touch with the osteoblastic lamina. At the end of the process, the osteocytes are confined to lacuno‐canalicular cavities, “prisoners”At the end inside of thethe process,mineralized the osteocytesmatrix. Despite are confined this fact, to they lacuno-canalicular are connected, thanks cavities, to “prisoners”the dendrogenesis inside the process, mineralized to each matrix. other Despiteand with this the fact, bone they cells are on connected, the vascular thanks surfaces to the dendrogenesisthrough a network process, of todendrities, each other running and with within the bone the cells canalicular on the vascular network; surfaces this condition through aallows network osteocytes of dendrities, to act as running “orchestrators” within the of bone canalicular processes network; [12,13]. this Prerequisite condition for allows that osteocytesis the existence to act of as junctional “orchestrators” complexes of bone occurring processes among [12 ,osteocyte13]. Prerequisite cytoplasmic for that processes is the existence[7,14,15], of suggesting junctional complexesthat the bone occurring cells of among the osteogenic osteocyte cytoplasmiclineage, arranged processes in [network7,14,15], suggesting(Figure 2), might that the act bone as a cells functional of the osteogenicsyncytium, lineage, that includes arranged also in the network cells covering (Figure 2the), mightvascular act bone as a functional surfaces, bone syncytium, lining cells that includes[15] or osteoblasts also the cells [16]. covering the vascular bone surfaces, bone lining cells [15] or osteoblasts [16]. In conclusion, throughout the whole differentiation process, preosteocytes are always in close relationship with the neighboring cells (osteoblasts, osteocytes) by means of variously-shaped intercellular contacts (invaginated finger-like, side-to-side, and end to- end) and two types of specialized junctions: gap and adherens [14]. The pivotal role played by these contacts and junctions in osteocyte differentiation and activity will be discussed in the context of their distinct functional significance. J. Funct. Morphol. Kinesiol. 2021, 6, 28 3 of 17 J. Funct. Morphol. Kinesiol. 2021, 6, x FOR PEER REVIEW 3 of 18 FigureFigure 2.2. Transmission electronelectron microscopemicroscope (TEM)(TEM) micrographmicrograph showing the continuous cytoplasmiccytoplas‐ mic network of the cells of the osteogenic lineage, extending from osteocytes to endothelial cells. network of the cells of the osteogenic lineage, extending