Osteocyte: Comparison
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Please note this is a comparison between Version 1 by Carla Palumbo and Version 2 by Vicky Zhou.

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.

  • osteocytes
  • bone mechano-sensor
  • skeletal homeostasis
  • mineral homeostasis
  • bone remodeling

1. Introduction

It has been known for more than a century [1][2][3] that the osteocyte originates from the osteoblast. However, the process of osteoblast-to-osteocyte differentiation has been widely 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 various authors in the 1960s to1980s [4][5][6][7][8], but only afterwards was established the temporal sequence of the events that allows the transformation of the prismatic osteoblast (generally arranged in laminae facing the vascular bone surfaces) into the dendritic mature osteocyte (embedded in the mineralized matrix) [9][10][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 with an asynchronous and asymmetric pattern, considering that the cells in differentiation are progressively further away from the vascular surface due to the osteoid secreted by the osteoblastic lamina (Figure 1): firstly, the differentiating osteocytes maintain contacts with the mature osteocytes that recruited them from the osteoblastic lamina, forming short “mineral” processes; later, they establish contacts 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 cells) live in an asymmetrical environment, between the mature mineralized matrix and the vascular surface (covered by osteoblastic laminae or bone lining cells); thus, it is logical to expect that not only the osteocytes, but also the preosteocytes and the osteoblasts, are morpho-functionally asymmetric cells.

Figure 1.

Schematic drawing showing the asynchronous and asymmetric pattern of cytoplasmic processes formation during osteocyte differentiation (preosteocytes = black; osteoblasts = white). (

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 but still in contact with the osteoblastic lamina, continues to radiate short and thick cytoplasmic processes only from its mineral-facing side. (

C

) Preosteocyte, before being completely buried by minerals, radiates 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” inside the mineralized matrix. Despite this fact, they are connected, thanks to the dendrogenesis process, to each other and with the bone cells on the vascular surfaces through a network of dendrities, running within the canalicular network; this condition allows osteocytes to act as “orchestrators” of bone processes [12][13]. Prerequisite for that is the existence of junctional complexes occurring among osteocyte cytoplasmic processes [7][14][15], suggesting that the bone cells of the osteogenic lineage, arranged in network (Figure 2), might act as a functional syncytium, that includes also the cells covering the vascular bone surfaces, bone lining cells [15] or osteoblasts [16].

Figure 2.

Transmission electron microscope (TEM) micrograph showing the continuous cytoplasmic network of the cells of the osteogenic lineage, extending from osteocytes to endothelial cells. (PO preosteocyte, OB osteoblast, SC stromal cell, EC endothelial cell). ×22,500.

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.

2. Interplay between Mineral and Skeletal Homeostasis and Osteocyte Role Mediated by Sclerostin

Bone remodeling is the main tool by which the skeleton answers to both the metabolic and mechanical demands, thus regulating the mineral and skeletal homeostasis. The mineral homeostasis keeps in relatively stable balance the concentration of mineral ions, as calcium and phosphate, in the organic liquids; the skeletal homeostasis allows the adjustment of shape, mass and bone structure following the actual mechanical needs of the skeletal segments. The two processes are not independent of each other; in fact, various investigations showed that they are functionally correlated in driving the bone responses, as a whole, to different experimental conditions

[17][18][19][20][21]

.
Here, the authors want to stress the importance of the interplay between mineral and skeletal homeostasis (i.e., a dynamic balance of the two homeostases) in modulating and guiding bone’s response to dietary/metabolic alterations and/or unbalance of loading conditions. In particular, it is important to be emphasized that mineral homeostasis involves bone response to a variation of mineral serum levels (in consequence of various conditions, such as hormonal alterations or dietary regimen), while skeletal homeostasis implies bone answers to loading modifications.
In metabolic osteoporosis due to a calcium-deprived diet for one month in a rat model, Ferretti and coworkers

[22]

showed that the lack of calcium in the diet does not lead to a unique bone answer, since the interplay between mineral and skeletal homeostasis influence the bone loss in different sites of the two bony architectures (trabecular versus cortical bone) in both axial (lumbar vertebrae) and appendicular (femurs) skeleton. Despite the observed reduction of trabecular number (due to the maintenance of mineral homeostasis), an intense activity of bone deposition occurs on the surface of the few remaining overloaded trabeculae (in answering to mechanical stresses and, consequently, to maintain the skeletal homeostasis). The authors also reported: (i) the evidence that the more involved bony architecture is the trabecular one, that is the most susceptible to dynamic homeostasis variations; (ii) the different responses recorded in different sites of cortical bone are dependent on their main function in answering mineral and/or skeletal homeostasis.
Moreover, on the basis of evidence that PTH(1-34) improves recovery of bone fragility and accelerates bone healing

[23][24][25][26][27][28][29]

, a recent study, performed by Ferretti and coworkers in animal models

[21]

, showed that, after one month of calcium-free feeding, the normal diet restoration with/without concomitant PTH (1-34) administration differently determines the pattern of bone mass recovery, in terms of amounts and sites, not only depending on the mineral homeostasis but also under the influence of the skeletal homeostasis. This study highlighted (i) the importance of the interplay between mineral and skeletal homeostasis, (ii) the evidence that the more involved bony architecture, in modulating and guiding bone’s response to dietary/metabolic alterations, is again the trabecular bone, (iii) the trabecular bone as the preferential target of PTH (1-34). These observations agree with those of various authors

[30][31][32]

showing that appendicular skeleton (mostly concerning cortical bone) answers mainly to mechanical demands (i.e., is devoted to the skeletal homeostasis) while axial skeleton (mostly concerning trabecular bone) answers mainly to metabolic demand (i.e., is mainly devoted to the mineral homeostasis).
With regard to the osteocyte’s role in mediating the interaction between the two types of homeostasis, it represents (as previously reported) both the bone mechano-sensor and the major producer of some signaling proteins. As previously mentioned, one of the most investigated osteocyte proteins is sclerostin, that inhibits osteoblast activity, depending (among other factors/conditions) on the answers to mineral and skeletal homeostasis. In this context, it is not surprising that sclerostin expression is higher in animals fed a calcium-free diet with respect to all animals with restored normal diet and to the control groups

[20]

, also depending on the answers to mineral and skeletal homeostasis

[33]

.

3. Conclusions

In conclusion, despite the “segregation” within the mineralized bone matrix, the osteocyte is the dynamic bone cellular element that triggers/guides/modulates a series of sophisticated and interconnected processes, in hierarchic priority: their balance is allowed by osteocyte capability to sense the different bone demands (i.e., metabolic, hormonal, mechanical, etc.) and, depending on the interaction with the actual systemic conditions, to act on the “operator” bone cells that form and destroyed bone tissue under the direction of the best orchestrator.

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