Harris, Teitelbaum & Carbone, Family Law (5th Ed., Aspen Press, 2014).

Os tissue is continuously remodeled through the concerted actions of bone cells, which include os resorption by osteoclasts and os formation by osteoblasts, whereas osteocytes deed as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (eastward.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between os resorption and formation can event in bone diseases including osteoporosis. Recently, information technology has been recognized that, during os remodeling, there are an intricate communication amongst bone cells. For instance, the coupling from bone resorption to bone germination is achieved by interaction betwixt osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic os resorption. The increasing noesis nigh the structure and functions of bone cells contributed to a meliorate understanding of os biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we hash out the current data about the construction and functions of bone cells and the factors that influence bone remodeling.

one. Introduction

Bone is a mineralized connective tissue that exhibits four types of cells: osteoblasts, os lining cells, osteocytes, and osteoclasts [1, 2]. Bone exerts of import functions in the torso, such as locomotion, back up and protection of soft tissues, calcium and phosphate storage, and harboring of bone marrow [3, iv]. Despite its inert appearance, bone is a highly dynamic organ that is continuously resorbed by osteoclasts and neoformed past osteoblasts. There is evidence that osteocytes human activity as mechanosensors and orchestrators of this bone remodeling process [five–8]. The function of os lining cells is not well clear, but these cells seem to play an important function in coupling bone resorption to bone formation [nine].

Os remodeling is a highly complex process by which old bone is replaced by new bone, in a cycle comprised of three phases: (1) initiation of bone resorption past osteoclasts, (two) the transition (or reversal flow) from resorption to new bone formation, and (iii) the bone formation by osteoblasts [10, 11]. This process occurs due to coordinated deportment of osteoclasts, osteoblasts, osteocytes, and os lining cells which together form the temporary anatomical structure called basic multicellular unit (BMU) [12–14].

Normal bone remodeling is necessary for fracture healing and skeleton adaptation to mechanical use, as well every bit for calcium homeostasis [fifteen]. On the other mitt, an imbalance of bone resorption and formation results in several bone diseases. For example, excessive resorption past osteoclasts without the corresponding amount of nerformed bone by osteoblasts contributes to bone loss and osteoporosis [16], whereas the contrary may outcome in osteopetrosis [17]. Thus, the equilibrium betwixt bone germination and resorption is necessary and depends on the action of several local and systemic factors including hormones, cytokines, chemokines, and biomechanical stimulation [xviii–xx].

Recent studies accept shown that bone influences the activity of other organs and the os is as well influenced by other organs and systems of the body [21], providing new insights and evidencing the complexity and dynamic nature of bone tissue.

In this review we will address the current data about bone cells biological science, bone matrix, and the factors that influence the bone remodeling process. Moreover, we will briefly hash out the role of estrogen on os tissue under physiological and pathological conditions.

2. Bone Cells

two.ane. Osteoblasts

Osteoblasts are cuboidal cells that are located along the bone surface comprising iv–half-dozen% of the total resident os cells and are largely known for their bone forming function [22]. These cells show morphological characteristics of protein synthesizing cells, including abundant rough endoplasmic reticulum and prominent Golgi apparatus, as well equally diverse secretory vesicles [22, 23]. Every bit polarized cells, the osteoblasts secrete the osteoid toward the bone matrix [24] (Figures 1(a), 1(b), and 2(a)).

(a)

(b)

Osteoblasts are derived from mesenchymal stem cells (MSC). The commitment of MSC towards the osteoprogenitor lineage requires the expression of specific genes, following timely programmed steps, including the synthesis of os morphogenetic proteins (BMPs) and members of the Wingless (Wnt) pathways [25]. The expressions of Runt-related transcription factors 2, Distal-less homeobox 5 (Dlx5), and osterix (Osx) are crucial for osteoblast differentiation [22, 26]. Additionally, Runx2 is a master gene of osteoblast differentiation, as demonstrated by the fact that Runx2-null mice are devoid of osteoblasts [26, 27]. Runx2 has demonstrated to upregulate osteoblast-related genes such as ColIA1, ALP, BSP, BGLAP, and OCN [28].

Once a pool of osteoblast progenitors expressing Runx2 and ColIA1 has been established during osteoblast differentiation, at that place is a proliferation phase. In this phase, osteoblast progenitors testify alkaline metal phosphatase (ALP) activity, and are considered preosteoblasts [22]. The transition of preosteoblasts to mature osteoblasts is characterized by an increase in the expression of Osx and in the secretion of os matrix proteins such as osteocalcin (OCN), bone sialoprotein (BSP) I/Ii, and collagen blazon I. Moreover, the osteoblasts undergo morphological changes, becoming large and cuboidal cells [26, 29–31].

At that place is evidence that other factors such as fibroblast growth factor (FGF), microRNAs, and connexin 43 play of import roles in the osteoblast differentiation [32–35]. FGF-ii knockout mice showed a decreased os mass coupled to increase of adipocytes in the bone marrow, indicating the participation of FGFs in the osteoblast differentiation [34]. It has also been demonstrated that FGF-18 upregulates osteoblast differentiation in an autocrine mechanism [36]. MicroRNAs are involved in the regulation of gene expression in many cell types, including osteoblasts, in which some microRNAs stimulate and others inhibit osteoblast differentiation [37, 38]. Connexin 43 is known to be the principal connexin in os [35]. The mutation in the gene encoding connexin 43 impairs osteoblast differentiation and causes skeletal malformation in mouse [39].

The synthesis of os matrix by osteoblasts occurs in ii main steps: deposition of organic matrix and its subsequent mineralization (Figures 1(b)–1(d)). In the first step, the osteoblasts secrete collagen proteins, mainly type I collagen, noncollagen proteins (OCN, osteonectin, BSP II, and osteopontin), and proteoglycan including decorin and biglycan, which form the organic matrix. Thereafter, mineralization of os matrix takes place into ii phases: the vesicular and the fibrillar phases [40, 41]. The vesicular phase occurs when portions with a variable diameter ranging from 30 to 200 nm, chosen matrix vesicles, are released from the apical membrane domain of the osteoblasts into the newly formed os matrix in which they bind to proteoglycans and other organic components. Because of its negative accuse, the sulphated proteoglycans immobilize calcium ions that are stored inside the matrix vesicles [41, 42]. When osteoblasts secrete enzymes that dethrone the proteoglycans, the calcium ions are released from the proteoglycans and cross the calcium channels presented in the matrix vesicles membrane. These channels are formed past proteins chosen annexins [40].

On the other hand, phosphate-containing compounds are degraded by the ALP secreted by osteoblasts, releasing phosphate ions inside the matrix vesicles. And then, the phosphate and calcium ions inside the vesicles nucleate, forming the hydroxyapatite crystals [43]. The fibrillar stage occurs when the supersaturation of calcium and phosphate ions inside the matrix vesicles leads to the rupture of these structures and the hydroxyapatite crystals spread to the surrounding matrix [44, 45].

Mature osteoblasts appear as a single layer of cuboidal cells containing arable rough endoplasmic reticulum and large Golgi complex (Figures 2(a) and iii(a)). Some of these osteoblasts show cytoplasmic processes towards the bone matrix and reach the osteocyte processes [46]. At this stage, the mature osteoblasts can undergo apoptosis or go osteocytes or bone lining cells [47, 48]. Interestingly, round/ovoid structures containing dense bodies and TUNEL-positive structures have been observed within osteoblast vacuoles. These findings suggest that besides professional phagocytes, osteoblasts are also able to engulf and degrade apoptotic bodies during alveolar bone formation [49].

2.ii. Bone Lining Cells

Bone lining cells are quiescent flat-shaped osteoblasts that comprehend the os surfaces, where neither bone resorption nor bone formation occurs [50]. These cells exhibit a sparse and flat nuclear profile; its cytoplasm extends forth the os surface and displays few cytoplasmic organelles such equally profiles of crude endoplasmic reticulum and Golgi appliance [50] (Figure 2(b)). Some of these cells show processes extending into canaliculi, and gap junctions are also observed between adjacent bone lining cells and between these cells and osteocytes [fifty, 51].

The secretory activeness of bone lining cells depends on the bone physiological condition, whereby these cells can reacquire their secretory activity, enhancing their size and adopting a cuboidal appearance [52]. Bone lining cells functions are not completely understood, but information technology has been shown that these cells prevent the straight interaction between osteoclasts and bone matrix, when bone resorption should not occur, and also participate in osteoclast differentiation, producing osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) [14, 53]. Moreover, the bone lining cells, together with other os cells, are an important component of the BMU, an anatomical construction that is present during the os remodeling cycle [9].

ii.3. Osteocytes

Osteocytes, which comprise 90–95% of the total bone cells, are the about arable and long-lived cells, with a lifespan of up to 25 years [54]. Different from osteoblasts and osteoclasts, which accept been defined by their respective functions during bone formation and bone resorption, osteocytes were earlier divers past their morphology and location. For decades, due to difficulties in isolating osteocytes from bone matrix led to the erroneous notion that these cells would exist passive cells, and their functions were misinterpreted [55]. The development of new technologies such as the identification of osteocyte-specific markers, new animal models, evolution of techniques for bone cell isolation and culture, and the establishment of phenotypically stable cell lines led to the improvement of the understanding of osteocyte biology. In fact, it has been recognized that these cells play numerous important functions in bone [8].

The osteocytes are located within lacunae surrounded past mineralized bone matrix, wherein they show a dendritic morphology [15, 55, 56] (Figures three(a)–3(d)). The morphology of embedded osteocytes differs depending on the os type. For case, osteocytes from trabecular bone are more rounded than osteocytes from cortical bone, which brandish an elongated morphology [57].

Osteocytes are derived from MSCs lineage through osteoblast differentiation. In this process, four recognizable stages accept been proposed: osteoid-osteocyte, preosteocyte, young osteocyte, and mature osteocyte [54]. At the end of a bone formation cycle, a subpopulation of osteoblasts becomes osteocytes incorporated into the bone matrix. This process is accompanied by conspicuous morphological and ultrastructural changes, including the reduction of the round osteoblast size. The number of organelles such as rough endoplasmic reticulum and Golgi apparatus decreases, and the nucleus-to-cytoplasm ratio increases, which correspond to a decrease in the protein synthesis and secretion [58].

During osteoblast/osteocyte transition, cytoplasmic procedure starts to emerge before the osteocytes take been encased into the bone matrix [22]. The mechanisms involved in the development of osteocyte cytoplasmic processes are non well understood. However, the protein E11/gp38, also called podoplanin may have an important part. E11/gp38 is highly expressed in embedding or recently embedded osteocytes, similarly to other cell types with dendritic morphology such equally podocytes, type Ii lung alveolar cells, and cells of the choroid plexus [59]. It has been suggested that E11/gp38 uses energy from GTPase activity to interact with cytoskeletal components and molecules involved in cell motility, whereby regulate actin cytoskeleton dynamics [lx, 61]. Appropriately, inhibition of E11/gp38 expression in osteocyte-like MLO-Y4 cells has been shown to cake dendrite elongation, suggesting that E11/gp38 is implicated in dendrite germination in osteocytes [59].

Once the stage of mature osteocyte totally entrapped within mineralized bone matrix is accomplished, several of the previously expressed osteoblast markers such as OCN, BSPII, collagen type I, and ALP are downregulated. On the other manus, osteocyte markers including dentine matrix poly peptide 1 (DMP1) and sclerostin are highly expressed [8, 62–64].

Whereas the osteocyte cell torso is located inside the lacuna, its cytoplasmic processes (up to 50 per each cell) cross tiny tunnels that originate from the lacuna infinite called canaliculi, forming the osteocyte lacunocanalicular system [65] (Figures 3(b)–3(d)). These cytoplasmic processes are connected to other neighboring osteocytes processes by gap junctions, as well as to cytoplasmic processes of osteoblasts and bone lining cells on the bone surface, facilitating the intercellular ship of small signaling molecules such equally prostaglandins and nitric oxide among these cells [66]. In addition, the osteocyte lacunocanalicular system is in close proximity to the vascular supply, whereby oxygen and nutrients achieve osteocytes [15].

Information technology has been estimated that osteocyte surface is 400-fold larger than that of the all Haversian and Volkmann systems and more than 100-fold larger than the trabecular bone surface [67, 68]. The jail cell-cell communication is also achieved by interstitial fluid that flows between the osteocytes processes and canaliculi [68]. By the lacunocanalicular system (Effigy 3(b)), the osteocytes act equally mechanosensors as their interconnected network has the capacity to detect mechanical pressures and loads, thereby helping the adaptation of bone to daily mechanical forces [55]. By this way, the osteocytes seem to act every bit orchestrators of os remodeling, through regulation of osteoblast and osteoclast activities [15, 69]. Moreover, osteocyte apoptosis has been recognized as a chemotactic betoken to osteoclastic bone resorption [70–73]. In agreement, information technology has been shown that during bone resorption, apoptotic osteocytes are engulfed by osteoclasts [74–76].

The mechanosensitive role of osteocytes is accomplished due to the strategic location of these cells inside bone matrix. Thus, the shape and spatial system of the osteocytes are in agreement with their sensing and point transport functions, promoting the translation of mechanical stimuli into biochemical signals, a phenomenon that is called piezoelectric effect [77]. The mechanisms and components by which osteocytes catechumen mechanical stimuli to biochemical signals are non well known. However, two mechanisms accept been proposed. One of them is that there is a protein complex formed by a cilium and its associated proteins PolyCystins 1 and 2, which has been suggested to be crucial for osteocyte mechanosensing and for osteoblast/osteocyte-mediated bone formation [78]. The second mechanism involves osteocyte cytoskeleton components, including focal adhesion protein complex and its multiple actin-associated proteins such every bit paxillin, vinculin, talin, and zyxin [79]. Upon mechanical stimulation, osteocytes produce several secondary messengers, for example, ATP, nitric oxide (NO), Ca^two+, and prostaglandins (PGE₂ and PGI_two,) which influence bone physiology [viii, 80]. Independently of the mechanism involved, it is important to mention that the mechanosensitive function of osteocytes is possible due to the intricate canalicular network, which allows the communication among bone cells.

ii.iv. Osteoclasts

Osteoclasts are terminally differentiated multinucleated cells (Figures iv(a)–4(d)), which originate from mononuclear cells of the hematopoietic stem cell lineage, under the influence of several factors. Amidst these factors the macrophage colony-stimulating factor (Chiliad-CSF), secreted by osteoprogenitor mesenchymal cells and osteoblasts [81], and RANK ligand, secreted by osteoblasts, osteocytes, and stromal cells, are included [20]. Together, these factors promote the activation of transcription factors [81, 82] and factor expression in osteoclasts [83, 84].

Thousand-CSF binds to its receptor (cFMS) nowadays in osteoclast precursors, which stimulates their proliferation and inhibits their apoptosis [82, 85]. RANKL is a crucial factor for osteoclastogenesis and is expressed past osteoblasts, osteocytes, and stromal cells. When it binds to its receptor RANK in osteoclast precursors, osteoclast formation is induced [86]. On the other hand, another factor called osteoprotegerin (OPG), which is produced by a wide range of cells including osteoblasts, stromal cells, and gingival and periodontal fibroblasts [87–89], binds to RANKL, preventing the RANK/RANKL interaction and, consequently, inhibiting the osteoclastogenesis [87] (Figure 5). Thus, the RANKL/RANK/OPG arrangement is a key mediator of osteoclastogenesis [nineteen, 86, 89].

The RANKL/RANK interaction as well promotes the expression of other osteoclastogenic factors such equally NFATc1 and DC-Postage. By interacting with the transcription factors PU.1, cFos, and MITF, NFATc1 regulates osteoclast-specific genes including TRAP and cathepsin Thou, which are crucial for osteoclast action [90]. Under the influence of the RANKL/RANK interaction, NFATc1 likewise induces the expression of DC-STAMP, which is crucial for the fusion of osteoclast precursors [91, 92].

Despite these osteoclastogenic factors having been well defined, information technology has recently been demonstrated that the osteoclastogenic potential may differ depending on the bone site considered. It has been reported that osteoclasts from long bone marrow are formed faster than in the jaw. This dissimilar dynamic of osteoclastogenesis possibly could be, due to the cellular composition of the bone-site specific marrow [93].

During bone remodeling osteoclasts polarize; then, 4 types of osteoclast membrane domains can be observed: the sealing zone and ruffled border that are in contact with the bone matrix (Figures 4(b) and iv(d)), equally well as the basolateral and functional secretory domains, which are non in contact with the bone matrix [94, 95]. Polarization of osteoclasts during bone resorption involves rearrangement of the actin cytoskeleton, in which an F-actin band that comprises a dense continuous zone of highly dynamic podosome is formed and consequently an area of membrane that develop into the ruffled border is isolated. Information technology is of import to mention that these domains are only formed when osteoclasts are in contact with extracellular mineralized matrix, in a process which -integrin, besides as the CD44, mediates the zipper of the osteoclast podosomes to the bone surface [96–99]. Ultrastructurally, the ruffled border is a membrane domain formed by microvilli, which is isolated from the surrounded tissue by the articulate zone, besides known as sealing zone. The clear zone is an area devoid of organelles located in the periphery of the osteoclast next to the bone matrix [98]. This sealing zone is formed past an actin band and several other proteins, including actin, talin, vinculin, paxillin, tensin, and actin-associated proteins such as α-actinin, fimbrin, gelsolin, and dynamin [95]. The -integrin binds to noncollagenous bone matrix containing-RGD sequence such as bone sialoprotein, osteopontin, and vitronectin, establishing a peripheric sealing that delimits the central region, where the ruffled border is located [98] (Figures four(b)–4(d)).

The maintenance of the ruffled border is besides essential for osteoclast activeness; this structure is formed due to intense trafficking of lysosomal and endosomal components. In the ruffled border, there is a vacuolar-type H⁺-ATPase (5-ATPase), which helps to acidify the resorption lacuna and hence to enable dissolution of hydroxyapatite crystals [20, 100, 101]. In this region, protons and enzymes, such as tartrate-resistant acrid phosphatase (TRAP), cathepsin 1000, and matrix metalloproteinase-9 (MMP-ix) are transported into a compartment called Howship lacuna leading to bone degradation [94, 101–104] (Figure 5). The products of this deposition are then endocytosed across the ruffled border and transcytosed to the functional secretory domain at the plasma membrane [7, 95].

Abnormal increment in osteoclast germination and activity leads to some bone diseases such as osteoporosis, where resorption exceeds formation causing decreased os density and increased bone fractures [105]. In some pathologic conditions including bone metastases and inflammatory arthritis, abnormal osteoclast activation results in periarticular erosions and painful osteolytic lesions, respectively [83, 105, 106]. In periodontitis, a affliction of the periodontium acquired by bacterial proliferation [107, 108] induces the migration of inflammatory cells. These cells produce chemical mediators such as IL-six and RANKL that stimulate the migration of osteoclasts [89, 109, 110]. As a result, an abnormal increased bone resorption occurs in the alveolar bone, contributing to the loss of the insertions of the teeth and to the progression of periodontitis [89, 111].

On the other manus, in osteopetrosis, which is a rare bone disease, genetic mutations that impact germination and resorption functions in osteoclasts lead to decreased bone resorption, resulting in a disproportionate aggregating of bone mass [17]. These diseases demonstrate the importance of the normal os remodeling process for the maintenance of bone homeostasis.

Furthermore, at that place is evidence that osteoclasts display several other functions. For example, it has been shown that osteoclasts produce factors called clastokines that command osteoblast during the bone remodeling cycle, which will be discussed beneath. Other recent testify is that osteoclasts may also directly regulate the hematopoietic stalk cell niche [112]. These findings indicate that osteoclasts are not only os resorbing cells, only besides a source of cytokines that influence the action of other cells.

2.5. Extracellular Bone Matrix

Bone is equanimous past inorganic salts and organic matrix [113]. The organic matrix contains collagenous proteins (90%), predominantly type I collagen, and noncollagenous proteins including osteocalcin, osteonectin, osteopontin, fibronectin and bone sialoprotein 2, bone morphogenetic proteins (BMPs), and growth factors [114]. There are also modest leucine-rich proteoglycans including decorin, biglycan, lumican, osteoaderin, and seric proteins [114–116].

The inorganic cloth of bone consists predominantly of phosphate and calcium ions; however, significant amounts of bicarbonate, sodium, potassium, citrate, magnesium, carbonate, fluorite, zinc, barium, and strontium are likewise present [1, two]. Calcium and phosphate ions nucleate to form the hydroxyapatite crystals, which are represented by the chemical formula Ca_ten(PO₄)₆(OH)₂. Together with collagen, the noncollagenous matrix proteins course a scaffold for hydroxyapatite deposition and such clan is responsible for the typical stiffness and resistance of bone tissue [4].

Os matrix constitutes a complex and organized framework that provides mechanical support and exerts essential function in the bone homeostasis. The bone matrix can release several molecules that interfere in the bone cells activity and, consequently, has a participation in the os remodeling [117]. Once loss of bone mass alone is insufficient to crusade bone fractures [118], information technology is suggested that other factors, including changes in the bone matrix proteins and their modifications, are of crucial importance to the agreement and prediction of bone fractures [119]. In fact, information technology is known that collagen plays a disquisitional part in the construction and function of bone tissue [120].

Accordingly, information technology has been demonstrated that at that place is a variation in the concentration of bone matrix proteins with historic period, diet, illness, and antiosteoporotic treatments [119, 121, 122] which may contribute to postyield deformation and fracture of bone [119]. For instance, in vivo and in vitro studies have reported that the increase in hyaluronic acid synthesis subsequently parathyroid hormone (PTH) treatment was related to a subsequent bone resorption [123–127] suggesting a possible human relationship between hyaluronic acid synthesis and the increase in osteoclast activeness.

ii.6. Interactions betwixt Bone Cells and Bone Matrix

As previously discussed, bone matrix does not only provides support for bone cells, but too has a key office in regulating the activeness of os cells through several adhesion molecules [117, 128]. Integrins are the most common adhesion molecules involved in the interaction between bone cells and bone matrix [129]. Osteoblasts make interactions with bone matrix by integrins, which recognize and bind to RGD and other sequences present in bone matrix proteins including osteopontin, fibronectin, collagen, osteopontin, and bone sialoprotein [130, 131]. The virtually common integrins present in osteoblasts are , , and [132]. These proteins also play an of import part in osteoblast organization on the bone surface during osteoid synthesis [129].

On the other manus, the interaction between osteoclasts and bone matrix is essential for osteoclast office, since equally previously mentioned, bone resorption occurs only when osteoclasts demark to mineralized os surface [97]. Thus, during bone resorption osteoclasts limited and integrins to collaborate with the extracellular matrix, in which the erstwhile bind to bone-enriched RGD-containing proteins, such equally os sialoprotein and osteopontin, whereas integrins demark to collagen fibrils [133, 134]. Despite these bindings, osteoclasts are highly motile even active resorption and, every bit migrating cells, osteoclasts practise not express cadherins. However, it has been demonstrated that cadherins provide intimate contact betwixt osteoclast precursors and stromal cells, which limited crucial growth factors for osteoclast differentiation [135].

Integrins play a mediating role in osteocyte-bone matrix interactions. These interactions are essential for the mechanosensitive part of these cells, whereby signals induced by tissue deformation are generated and amplified [136]. It is nonetheless not clear which integrins are involved, but it has been suggested that and integrins are involved in osteocyte-bone matrix interaction [137, 138]. These interactions occur between osteocyte body and the bone matrix of the lacuna wall too as between canalicular wall with the osteocyte processes [137].

Just a narrow pericellular infinite filled by a fluid separates the osteocyte cell body and processes from a mineralized os matrix [58]. The infinite betwixt osteocyte jail cell trunk and the lacunar wall is approximately 0.5–1.0μthou wide, whereas the altitude between the membranes of osteocyte processes and the canalicular wall varies from 50 to 100 nm [139]. The chemical limerick of the pericellular fluid has not been precisely defined. However, a diverse array of macromolecules produced by osteocytes such as osteopontin, osteocalcin, dentin matrix poly peptide, proteoglycans, and hyaluronic acid is present [136, 140, 141].

The osteocyte and their processes are surrounded by a nonorganized pericellular matrix; delicate fibrous connections were observed within the canalicular network, termed "tethers" [139]. Information technology has been suggested that perlecan is a possible chemical compound of these tethers [141]. Osteocyte processes tin can also attach directly by the "hillocks," which are protruding structures originating from the canalicular walls. These structures grade close contacts, possibly by ways of -integrins, with the membrane of osteocyte processes [137, 142]. Thus, these structures seem to play a key role in the mechanosensitive function of osteocytes, by sensing the fluid flux movements along with the pericellular space, provoked past mechanical load forces [143]. In addition, the fluid flux movement is also essential for the bidirectional solute send in the pericellular space, which influences osteocyte signaling pathways and advice among bone cells [144, 145].

2.vii. Local and Systemic Factor That Regulate Bone Homeostasis

Bone remodeling is a highly complex cycle that is achieved by the concerted actions of osteoblasts, osteocytes, osteoclasts, and bone lining cells [3]. The formation, proliferation, differentiation, and action of these cells are controlled by local and systemic factors [18, 19]. The local factors include autocrine and paracrine molecules such every bit growth factors, cytokines, and prostaglandins produced by the bone cells besides factors of the bone matrix that are released during bone resorption [46, 146]. The systemic factors which are important to the maintenance of bone homeostasis include parathyroid hormone (PTH), calcitonin, 1,25-dihydroxyvitamin D_three (calcitriol), glucocorticoids, androgens, and estrogens [16, 147–150]. Similar to PTH, PTH related protein (PTHrP), which also binds to PTH receptor, has also been reported to influence bone remodeling [147].

Estrogen plays crucial roles for bone tissue homeostasis; the decrease in estrogen level at menopause is the main crusade of bone loss and osteoporosis [16]. The mechanisms past which estrogen act on os tissue are non completely understood. Nevertheless, several studies accept shown that estrogen maintains bone homeostasis by inhibiting osteoblast and osteocyte apoptosis [151–153] and preventing excessive bone resorption. The estrogen suppresses the osteoclast germination and activity as well equally induces osteoclast apoptosis [xvi, 76, 104, 154]. It has been suggested that estrogen decreases osteoclast formation by inhibiting the synthesis of the osteoclastogenic cytokine RANKL by osteoblasts and osteocytes. Moreover, estrogen stimulates these bone cells to produce osteoprotegerin (OPG), a decoy receptor of RANK in osteoclast, thus inhibiting osteoclastogenesis [19, 155–159]. In addition, estrogen inhibits osteoclast germination by reducing the levels of other osteoclastogenic cytokines such equally IL-ane, IL-half-dozen, IL-11, TNF-α, TNF-β, and Yard-CSF [160, 161].

Estrogen acts directly on bone cells past its estrogen receptors α and β present on these cells [162]. Moreover, information technology has been shown that osteoclast is a direct target for estrogen [163, 164]. Appropriately, immunoexpression of estrogen receptor β has been demonstrated in alveolar bone cells of estradiol-treated female rats. Moreover, the enhanced immunoexpression observed in TUNEL-positive osteoclasts indicates that estrogen participates in the control of osteoclast life span directly by estrogen receptors [163]. These findings demonstrate the importance of estrogen for the maintenance of bone homeostasis.

2.8. Bone Remodeling Procedure

The bone remodeling bicycle takes place within os cavities that need to be remodeled [165]. In these cavities, there is the formation of temporary anatomical structures called bones multicellular units (BMUs), which are comprised of a grouping of osteoclasts ahead forming the cutting cone and a group of osteoblasts backside forming the closing cone, associated with blood vessels and the peripheral innervation [11, 166]. It has been suggested that BMU is covered by a awning of cells (maybe bone lining cells) that form the os remodeling compartment (BRC) [13]. The BRC seems to be continued to bone lining cells on os surface, which in turn are in advice with osteocytes enclosed within the bone matrix [13, 14].

The bone remodeling cycle begins with an initiation phase, which consists of bone resorption by osteoclasts, followed by a phase of bone formation by osteoblasts but between these two phases, at that place is a transition (or reversal) phase. The wheel is completed past coordinated deportment of osteocytes and bone lining cells [10, eleven]. In the initiation phase, under the action of osteoclastogenic factors including RANKL and M-CSF, hematopoietic stalk cells are recruited to specific bone surface areas and differentiate into mature osteoclasts that initiate os resorption [167, 168].

Information technology is known that during bone remodeling cycle, there are direct and indirect communications among bone cells in a procedure called coupling mechanism, which include soluble coupling factors stored in bone matrix that would be released after osteoclast os resorption [169]. For instance, factors such as insulin-like growth factors (IGFs), transforming growth factor β (TGF-β), BMPs, FGF, and platelet-derived growth factor (PDGF) seem to act equally coupling factors, since they are stored in bone matrix and released during bone resorption [170]. This idea is supported by genetic studies in humans and mice every bit well as past pharmacological studies [105, 171].

Recently, it has been suggested that another category of molecules called semaphorins is involved in the bone cell advice during os remodeling [146]. During the initial phase, osteoblast differentiation and activity must be inhibited, in gild to completely remove the damaged or aged bone. The osteoclasts express a factor called semaphorin4D (Sema4D) that inhibits bone formation during os resorption [172]. Semaphorins comprise a large family of glycoproteins which are not but membrane-spring merely also be as soluble forms that are found in a wide range of tissues and shown to be involved in diverse biological processes such as allowed response, organogenesis, cardiovascular development, and tumor progression [172, 173]. In bone, it has been suggested that semaphorins are also involved in cell-jail cell communication between osteoclasts and osteoblasts during the bone remodeling cycle [174–176].

Sema4D expressed in osteoclasts binds to its receptor (Plexin-B1) present in osteoblasts and inhibits IGF-1 pathway, essential for osteoblast differentiation [172], suggesting that osteoclasts suppress bone germination by expressing Sema4D. Conversely, another member of semaphorin family (Sema3A) has been institute in osteoblasts and is considered an inhibitor of osteoclastogenesis [177]. Thus, during the bone remodeling cycle, osteoclasts inhibit bone formation past expressing Sema4D, in club to initiate bone resorption, whereas osteoblasts express Sema3A that suppresses bone resorption, prior to bone germination [146] (Figure v).

Recent studies also suggest the existence of other factors involved in the coupling mechanism during the os remodeling bike. I of these factors is ephrinB2, a membrane-leap molecule expressed in mature osteoclasts, which bind to ephrinB4, found in the plasma membrane of osteoblasts. The ephrinB2/ephrinB4 binding transduces bidirectional signals, which promote osteoblast differentiation, whereas the contrary signaling (ephrinB4/ephrinB2) inhibits osteoclastogenesis [178] (Effigy 5). These findings suggest that ephrinB2/ephrinB4 pathway may be involved in the catastrophe of os resorption and induces osteoblast differentiation in the transition phase [178].

In improver, information technology has been shown that ephrinB2 is also expressed in osteoblasts [179]. Furthermore, mature osteoclasts secrete a number of factors that stimulate osteoblast differentiation such equally the secreted signaling molecules Wnt10b, BMP6, and the signaling sphingolipid, sphingosine-1-phosphate [180]. These findings suggest a highly complex machinery of ephrins and the involvement of other factors in osteoclast/osteoblast communication during the bone remodeling cycle. On the other hand, despite the studies reporting the involvement of semaphorins and ephrins on osteoclast/osteoblast communication, the direct contact between mature osteoblasts and osteoclasts has not been demonstrated in vivo and it is still controversial.

Besides osteoclasts and osteoblasts, it has been demonstrated that osteocytes play key roles during the os remodeling cycle [8]. In fact, under the influence of several factors, the osteocytes act as orchestrators of the bone remodeling process, producing factors that influence osteoblast and osteoclast activities [55] (Figure 5). For example, mechanical loading stimulates osteocyte to produce factors that exert anabolic action on bone such as PGE_two, prostacyclin (PGI₂), NO, and IGF-1 [181–184]. On the other hand, mechanical unloading downregulates anabolic factors and stimulates osteocytes to produce sclerostin and DKK-one, which are inhibitors of osteoblast activity [185–188], as well as specific factors that stimulate local osteoclastogenesis [189]. Sclerostin is a production of the SOST gene and is known to be a negative regulator of bone germination, by antagonizing in osteoblasts the deportment of Lrp5, a fundamental receptor of the Wnt/β-catenin signaling pathway [63].

Osteocyte apoptosis has been shown to act as a chemotactic signal for local osteoclast recruitment [70, 150, 152, 190, 191]. Appropriately, it has been reported that osteoclasts engulf apoptotic osteocytes [74, 75, 192], suggesting that osteoclasts are able to remove dying osteocytes and/or osteoblasts from a remodeling site (Figures 4(c) and iv(d)). Moreover, information technology is reported that the osteoclastogenic factors is as well produced past viable osteocytes nearby the dying osteocytes [193]. There is evidence that osteocytes act equally the primary source of RANKL to promote osteoclastogenesis [167, 168], although this factor has likewise been demonstrated to exist produced past other cell types such as stromal cells [194], osteoblasts, and fibroblasts [88, 89].

Thus, at that place are however uncertainties about the precise osteoclastogenesis-stimulating factors produced by osteocytes. Recent reviews have focused on some molecules that may exist candidates for signaling betwixt osteocyte apoptosis and osteoclastogenesis [72, 73]. For instance, in basic subjected to fatigue loading, viable osteocytes near the apoptotic ones express, besides loftier RANKL/OPG ratio, increased levels of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (CCL2) promoting an increase in local osteoclastogenesis [194, 195]. It has been suggested that osteocytes act as the chief source of RANKL to promote osteoclastogenesis [166, 167]. In add-on, an increase in RANKL/OPG ratio expressed by osteocytes was likewise observed in connexin43-deficient rats, suggesting that a disruption in cell-to-cell advice between osteocytes may induce the release of local proosteoclastogenic cytokines [33, 196, 197]. High mobility group box protein 1 (HMGB1) [198–200] and M-CSF [201] have also been suggested to be produced past osteocytes that stimulate osteoclast recruitment during bone remodeling [72, 73]. Thus, future studies are required to address this issue.

2.9. Endocrine Functions of Os Tissue

The classical functions of bone tissue, also locomotion, include support and protection of soft tissues, calcium, and phosphate storage and harboring of os marrow. Additionally, recent studies have focused on the bone endocrine functions which are able to affect other organs [202]. For instance, osteocalcin produced by osteoblasts has been shown to act in other organs [203]. Osteocalcin tin be found in two different forms: carboxylated and undercarboxylated. The carboxylated grade has high affinity to the hydroxyapatite crystals, remaining into os matrix during its mineralization. The undercarboxylated form shows lower affinity to minerals, due to acidification of os matrix during osteoclast os resorption, and so it is ferried by the bloodstream, reaching other organs [204, 205]. It has been shown that the undercarboxylated osteocalcin has some furnishings in pancreas, adipose tissue, testis, and the nervous system. In the pancreas, osteocalcin acts as a positive regulator of pancreatic insulin secretion and sensitivity also as for the proliferation of pancreatic β-cells [110]. In the adipose tissue, osteocalcin stimulates adiponectin gene expression that in turn enhances insulin sensitivity [204]. In the testis, osteocalcin tin bind to a specific receptor in Leydig cells and enhances testosterone synthesis and, consequently, increases fertility [206]. Osteocalcin also stimulates the synthesis of monoamine neurotransmitters in the hippocampus and inhibits gamma-aminobutyric acrid (GABA) synthesis, improving learning and memory skills [207].

Another endocrine function of bone tissue is promoted by osteocytes. These cells are able to regulate phosphate metabolism by the product of FGF23, which acts on other organs including parathyroid gland and kidneys to reduce the circulating levels of phosphates [208, 209]. Osteocytes also act on the immune organisation by modifying the microenvironment in primary lymphoid organs and thereby influencing lymphopoiesis [210]. Not only osteocyte but also osteoblast and osteoclast activities are known to influence the allowed system, mainly upon bone inflammatory destruction. Indeed, the discovery of advice interplay between skeletal and allowed systems led to a new field of study called osteoimmunology [211].

3. Conclusions

The noesis of the structural, molecular, and functional biology of bone is essential for the ameliorate comprehension of this tissue every bit a multicellular unit and a dynamic structure that tin can also act as an endocrine tissue, a function however poorly understood. In vitro and in vivo studies have demonstrated that bone cells respond to unlike factors and molecules, contributing to the better understanding of bone cells plasticity. Additionally, bone matrix integrins-dependent bone cells interactions are essential for os formation and resorption. Studies have addressed the importance of the lacunocanalicular arrangement and the pericellular fluid, by which osteocytes deed as mechanosensors, for the adaptation of bone to mechanical forces. Hormones, cytokines, and factors that regulate bone cells activity, such as sclerostin, ephrinB2, and semaphoring, have played a significant role in the os histophysiology under normal and pathological conditions. Thus, such deeper understanding of the dynamic nature of bone tissue volition certainly help to manage new therapeutic approaches to bone diseases.

Conflict of Interests

The authors declare that in that location is no disharmonize of interests regarding the publication of this paper.

Acknowledgments

This research was supported past Fundação de Amparo à Pesquisa practice Estado de São Paulo (FAPESP-2010/10391-ix; 2012/19428-8, and 2012/22666-eight), Conselho Nacional de Desenvolvimento Científico eastward Tecnológico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.

Copyright

Copyright © 2015 Rinaldo Florencio-Silva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted apply, distribution, and reproduction in any medium, provided the original work is properly cited.

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Source: https://www.hindawi.com/journals/bmri/2015/421746/

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