which component of bone tissue makes bone hard
Bone tissue is continuously remodeled through the concerted actions of bone cells, which include os resorption past osteoclasts and bone formation past osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is nether the control of local (e.yard., growth factors and cytokines) and systemic (e.thou., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and germination can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication amongst os cells. For instance, the coupling from os resorption to os formation is achieved past interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic os resorption. The increasing knowledge well-nigh the structure and functions of os cells contributed to a better agreement of bone biology. It has been suggested that there is a complex advice between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current information about the structure and functions of os cells and the factors that influence os remodeling.
i. Introduction
Os is a mineralized connective tissue that exhibits four types of cells: osteoblasts, bone lining cells, osteocytes, and osteoclasts [1, 2]. Os exerts important functions in the torso, such as locomotion, support and protection of soft tissues, calcium and phosphate storage, and harboring of bone marrow [3, 4]. 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 action as mechanosensors and orchestrators of this bone remodeling process [v–eight]. The function of os lining cells is non well clear, simply these cells seem to play an of import role in coupling os resorption to bone formation [9].
Bone remodeling is a highly complex process by which onetime bone is replaced past new os, in a bicycle comprised of 3 phases: (i) initiation of bone resorption by osteoclasts, (2) the transition (or reversal period) from resorption to new bone formation, and (3) the bone formation by osteoblasts [10, eleven]. This process occurs due to coordinated actions of osteoclasts, osteoblasts, osteocytes, and bone lining cells which together grade the temporary anatomical structure chosen bones multicellular unit (BMU) [12–14].
Normal bone remodeling is necessary for fracture healing and skeleton adaptation to mechanical use, likewise every bit for calcium homeostasis [15]. On the other paw, an imbalance of os resorption and germination results in several os diseases. For example, excessive resorption by osteoclasts without the corresponding amount of nerformed bone by osteoblasts contributes to bone loss and osteoporosis [16], whereas the contrary may result in osteopetrosis [17]. Thus, the equilibrium between bone germination and resorption is necessary and depends on the action of several local and systemic factors including hormones, cytokines, chemokines, and biomechanical stimulation [18–20].
Contempo studies have shown that bone influences the activity of other organs and the bone is besides 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 nosotros volition accost the current data about bone cells biology, bone matrix, and the factors that influence the bone remodeling process. Moreover, we will briefly talk over the part of estrogen on bone tissue under physiological and pathological atmospheric condition.
2. Bone Cells
2.1. Osteoblasts
Osteoblasts are cuboidal cells that are located forth the bone surface comprising iv–6% of the full resident os cells and are largely known for their bone forming function [22]. These cells bear witness morphological characteristics of protein synthesizing cells, including abundant rough endoplasmic reticulum and prominent Golgi appliance, likewise as various 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 delivery of MSC towards the osteoprogenitor lineage requires the expression of specific genes, post-obit timely programmed steps, including the synthesis of bone morphogenetic proteins (BMPs) and members of the Wingless (Wnt) pathways [25]. The expressions of Runt-related transcription factors two, Distal-less homeobox 5 (Dlx5), and osterix (Osx) are crucial for osteoblast differentiation [22, 26]. Additionally, Runx2 is a primary gene of osteoblast differentiation, as demonstrated by the fact that Runx2-zero 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 show alkaline phosphatase (ALP) activeness, and are considered preosteoblasts [22]. The transition of preosteoblasts to mature osteoblasts is characterized past an increase in the expression of Osx and in the secretion of bone matrix proteins such every bit osteocalcin (OCN), os sialoprotein (BSP) I/2, and collagen blazon I. Moreover, the osteoblasts undergo morphological changes, becoming big and cuboidal cells [26, 29–31].
In that location 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-2 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 cistron 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 main 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 two main steps: deposition of organic matrix and its subsequent mineralization (Figures 1(b)–ane(d)). In the first pace, the osteoblasts secrete collagen proteins, mainly type I collagen, noncollagen proteins (OCN, osteonectin, BSP II, and osteopontin), and proteoglycan including decorin and biglycan, which class the organic matrix. Thereafter, mineralization of bone matrix takes place into 2 phases: the vesicular and the fibrillar phases [40, 41]. The vesicular phase occurs when portions with a variable diameter ranging from xxx to 200 nm, called matrix vesicles, are released from the apical membrane domain of the osteoblasts into the newly formed bone matrix in which they demark 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 degrade 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 by proteins called annexins [twoscore].
On the other hand, phosphate-containing compounds are degraded by the ALP secreted by osteoblasts, releasing phosphate ions inside the matrix vesicles. And so, the phosphate and calcium ions within the vesicles nucleate, forming the hydroxyapatite crystals [43]. The fibrillar phase 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 abundant rough endoplasmic reticulum and big Golgi complex (Figures 2(a) and 3(a)). Some of these osteoblasts show cytoplasmic processes towards the bone matrix and achieve the osteocyte processes [46]. At this phase, the mature osteoblasts can undergo apoptosis or become osteocytes or bone lining cells [47, 48]. Interestingly, circular/ovoid structures containing dense bodies and TUNEL-positive structures have been observed within osteoblast vacuoles. These findings advise that likewise professional phagocytes, osteoblasts are also able to engulf and dethrone apoptotic bodies during alveolar bone formation [49].
2.2. Bone Lining Cells
Os lining cells are quiescent flat-shaped osteoblasts that cover the os surfaces, where neither os resorption nor bone formation occurs [50]. These cells showroom a thin and flat nuclear profile; its cytoplasm extends along the bone surface and displays few cytoplasmic organelles such as profiles of rough endoplasmic reticulum and Golgi apparatus [50] (Effigy 2(b)). Some of these cells show processes extending into canaliculi, and gap junctions are besides observed between adjacent bone lining cells and between these cells and osteocytes [fifty, 51].
The secretory action of os lining cells depends on the bone physiological status, whereby these cells tin reacquire their secretory activity, enhancing their size and adopting a cuboidal appearance [52]. Bone lining cells functions are non completely understood, but it has been shown that these cells prevent the direct interaction between osteoclasts and bone matrix, when os resorption should not occur, and too 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 bone cells, are an important component of the BMU, an anatomical structure that is present during the bone remodeling cycle [9].
2.3. Osteocytes
Osteocytes, which comprise 90–95% of the total bone cells, are the nigh arable and long-lived cells, with a lifespan of up to 25 years [54]. Different from osteoblasts and osteoclasts, which have been divers past their respective functions during bone formation and bone resorption, osteocytes were earlier defined by their morphology and location. For decades, due to difficulties in isolating osteocytes from bone matrix led to the erroneous notion that these cells would be passive cells, and their functions were misinterpreted [55]. The development of new technologies such every bit 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 inside lacunae surrounded by mineralized bone matrix, wherein they show a dendritic morphology [xv, 55, 56] (Figures three(a)–iii(d)). The morphology of embedded osteocytes differs depending on the bone blazon. For instance, osteocytes from trabecular os are more rounded than osteocytes from cortical bone, which display an elongated morphology [57].
Osteocytes are derived from MSCs lineage through osteoblast differentiation. In this process, four recognizable stages have been proposed: osteoid-osteocyte, preosteocyte, young osteocyte, and mature osteocyte [54]. At the finish of a os germination cycle, a subpopulation of osteoblasts becomes osteocytes incorporated into the bone matrix. This procedure 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 process starts to emerge before the osteocytes accept been encased into the os matrix [22]. The mechanisms involved in the development of osteocyte cytoplasmic processes are not well understood. However, the protein E11/gp38, also chosen podoplanin may have an important function. E11/gp38 is highly expressed in embedding or recently embedded osteocytes, similarly to other prison 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 [60, 61]. Appropriately, inhibition of E11/gp38 expression in osteocyte-similar MLO-Y4 cells has been shown to block dendrite elongation, suggesting that E11/gp38 is implicated in dendrite germination in osteocytes [59].
Once the stage of mature osteocyte totally entrapped within mineralized os matrix is accomplished, several of the previously expressed osteoblast markers such as OCN, BSPII, collagen type I, and ALP are downregulated. On the other hand, osteocyte markers including dentine matrix poly peptide 1 (DMP1) and sclerostin are highly expressed [viii, 62–64].
Whereas the osteocyte cell body is located inside the lacuna, its cytoplasmic processes (upwards to 50 per each cell) cross tiny tunnels that originate from the lacuna space called canaliculi, forming the osteocyte lacunocanalicular system [65] (Figures 3(b)–iii(d)). These cytoplasmic processes are connected to other neighboring osteocytes processes by gap junctions, likewise as to cytoplasmic processes of osteoblasts and bone lining cells on the bone surface, facilitating the intercellular transport of modest signaling molecules such as prostaglandins and nitric oxide among these cells [66]. In improver, the osteocyte lacunocanalicular organisation is in shut proximity to the vascular supply, whereby oxygen and nutrients achieve osteocytes [fifteen].
It has been estimated that osteocyte surface is 400-fold larger than that of the all Haversian and Volkmann systems and more 100-fold larger than the trabecular bone surface [67, 68]. The prison cell-cell advice is also achieved past interstitial fluid that flows between the osteocytes processes and canaliculi [68]. By the lacunocanalicular arrangement (Figure iii(b)), the osteocytes deed as mechanosensors as their interconnected network has the chapters to detect mechanical pressures and loads, thereby helping the adaptation of bone to daily mechanical forces [55]. By this style, the osteocytes seem to human activity as orchestrators of bone remodeling, through regulation of osteoblast and osteoclast activities [15, 69]. Moreover, osteocyte apoptosis has been recognized as a chemotactic signal to osteoclastic bone resorption [70–73]. In agreement, it has been shown that during bone resorption, apoptotic osteocytes are engulfed past osteoclasts [74–76].
The mechanosensitive function of osteocytes is accomplished due to the strategic location of these cells within os matrix. Thus, the shape and spatial system of the osteocytes are in agreement with their sensing and signal transport functions, promoting the translation of mechanical stimuli into biochemical signals, a miracle that is called piezoelectric issue [77]. The mechanisms and components by which osteocytes convert mechanical stimuli to biochemical signals are not well known. However, two mechanisms have been proposed. One of them is that there is a protein complex formed by a cilium and its associated proteins PolyCystins 1 and two, which has been suggested to be crucial for osteocyte mechanosensing and for osteoblast/osteocyte-mediated os formation [78]. The second mechanism involves osteocyte cytoskeleton components, including focal adhesion protein complex and its multiple actin-associated proteins such equally paxillin, vinculin, talin, and zyxin [79]. Upon mechanical stimulation, osteocytes produce several secondary messengers, for example, ATP, nitric oxide (NO), Ca2+, and prostaglandins (PGE2 and PGI2,) which influence bone physiology [viii, eighty]. 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 amid bone cells.
ii.4. Osteoclasts
Osteoclasts are terminally differentiated multinucleated cells (Figures iv(a)–iv(d)), which originate from mononuclear cells of the hematopoietic stem prison cell lineage, nether the influence of several factors. Among these factors the macrophage colony-stimulating gene (M-CSF), secreted past 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 gene expression in osteoclasts [83, 84].
M-CSF binds to its receptor (cFMS) present in osteoclast precursors, which stimulates their proliferation and inhibits their apoptosis [82, 85]. RANKL is a crucial factor for osteoclastogenesis and is expressed by osteoblasts, osteocytes, and stromal cells. When it binds to its receptor RANK in osteoclast precursors, osteoclast formation is induced [86]. On the other mitt, another factor chosen 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 five). Thus, the RANKL/RANK/OPG arrangement is a fundamental mediator of osteoclastogenesis [19, 86, 89].
The RANKL/RANK interaction also promotes the expression of other osteoclastogenic factors such as NFATc1 and DC-Postage. By interacting with the transcription factors PU.1, cFos, and MITF, NFATc1 regulates osteoclast-specific genes including TRAP and cathepsin Thousand, which are crucial for osteoclast activity [90]. Under the influence of the RANKL/RANK interaction, NFATc1 besides 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, it has recently been demonstrated that the osteoclastogenic potential may differ depending on the os site considered. Information technology 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 os-site specific marrow [93].
During bone remodeling osteoclasts polarize; then, four types of osteoclast membrane domains can be observed: the sealing zone and ruffled border that are in contact with the bone matrix (Figures four(b) and iv(d)), as well equally the basolateral and functional secretory domains, which are not in contact with the bone matrix [94, 95]. Polarization of osteoclasts during os resorption involves rearrangement of the actin cytoskeleton, in which an F-actin ring that comprises a dense continuous zone of highly dynamic podosome is formed and consequently an expanse of membrane that develop into the ruffled edge is isolated. It is important to mention that these domains are only formed when osteoclasts are in contact with extracellular mineralized matrix, in a procedure which -integrin, likewise 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 clear zone, also known as sealing zone. The articulate 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 by 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 every bit os sialoprotein, osteopontin, and vitronectin, establishing a peripheric sealing that delimits the central region, where the ruffled border is located [98] (Figures 4(b)–four(d)).
The maintenance of the ruffled border is also essential for osteoclast activity; this construction is formed due to intense trafficking of lysosomal and endosomal components. In the ruffled border, there is a vacuolar-blazon 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 acid phosphatase (TRAP), cathepsin Chiliad, and matrix metalloproteinase-9 (MMP-nine) are transported into a compartment called Howship lacuna leading to bone deposition [94, 101–104] (Figure 5). The products of this deposition are then endocytosed beyond the ruffled edge and transcytosed to the functional secretory domain at the plasma membrane [vii, 95].
Aberrant increase in osteoclast germination and activeness leads to some os diseases such as osteoporosis, where resorption exceeds formation causing decreased bone density and increased bone fractures [105]. In some pathologic conditions including bone metastases and inflammatory arthritis, aberrant osteoclast activation results in periarticular erosions and painful osteolytic lesions, respectively [83, 105, 106]. In periodontitis, a disease of the periodontium caused by bacterial proliferation [107, 108] induces the migration of inflammatory cells. These cells produce chemical mediators such equally IL-6 and RANKL that stimulate the migration of osteoclasts [89, 109, 110]. Equally a result, an abnormal increased bone resorption occurs in the alveolar os, contributing to the loss of the insertions of the teeth and to the progression of periodontitis [89, 111].
On the other hand, in osteopetrosis, which is a rare bone disease, genetic mutations that affect formation and resorption functions in osteoclasts atomic number 82 to decreased os resorption, resulting in a disproportionate accumulation of os mass [17]. These diseases demonstrate the importance of the normal os remodeling process for the maintenance of os homeostasis.
Furthermore, there is prove that osteoclasts display several other functions. For instance, it has been shown that osteoclasts produce factors chosen clastokines that command osteoblast during the os remodeling bicycle, which will exist discussed below. Other contempo show is that osteoclasts may also directly regulate the hematopoietic stem prison cell niche [112]. These findings point that osteoclasts are non only bone resorbing cells, only also a source of cytokines that influence the activity of other cells.
2.5. Extracellular Os Matrix
Bone is composed by inorganic salts and organic matrix [113]. The organic matrix contains collagenous proteins (xc%), predominantly type I collagen, and noncollagenous proteins including osteocalcin, osteonectin, osteopontin, fibronectin and os sialoprotein II, bone morphogenetic proteins (BMPs), and growth factors [114]. At that place are also small leucine-rich proteoglycans including decorin, biglycan, lumican, osteoaderin, and seric proteins [114–116].
The inorganic textile of bone consists predominantly of phosphate and calcium ions; notwithstanding, pregnant amounts of bicarbonate, sodium, potassium, citrate, magnesium, carbonate, fluorite, zinc, barium, and strontium are also present [ane, 2]. Calcium and phosphate ions nucleate to form the hydroxyapatite crystals, which are represented past the chemical formula Ca10(PO4)6(OH)2. Together with collagen, the noncollagenous matrix proteins form a scaffold for hydroxyapatite deposition and such association is responsible for the typical stiffness and resistance of bone tissue [four].
Bone matrix constitutes a complex and organized framework that provides mechanical support and exerts essential role 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 bone remodeling [117]. One time loss of os mass alone is bereft to crusade bone fractures [118], it is suggested that other factors, including changes in the bone matrix proteins and their modifications, are of crucial importance to the understanding and prediction of bone fractures [119]. In fact, it is known that collagen plays a critical office in the structure and function of os tissue [120].
Accordingly, it has been demonstrated that there is a variation in the concentration of bone matrix proteins with age, nutrition, disease, and antiosteoporotic treatments [119, 121, 122] which may contribute to postyield deformation and fracture of bone [119]. For example, in vivo and in vitro studies have reported that the increase in hyaluronic acrid synthesis after parathyroid hormone (PTH) treatment was related to a subsequent bone resorption [123–127] suggesting a possible relationship between hyaluronic acid synthesis and the increase in osteoclast activeness.
2.6. Interactions between Bone Cells and Bone Matrix
Equally previously discussed, bone matrix does not only provides support for bone cells, simply likewise has a key office in regulating the activity of bone cells through several adhesion molecules [117, 128]. Integrins are the almost mutual adhesion molecules involved in the interaction between os cells and bone matrix [129]. Osteoblasts make interactions with bone matrix by integrins, which recognize and demark to RGD and other sequences nowadays in bone matrix proteins including osteopontin, fibronectin, collagen, osteopontin, and os sialoprotein [130, 131]. The most mutual integrins present in osteoblasts are , , and [132]. These proteins likewise play an important function in osteoblast organization on the bone surface during osteoid synthesis [129].
On the other mitt, the interaction between osteoclasts and bone matrix is essential for osteoclast function, since as previously mentioned, bone resorption occurs only when osteoclasts bind to mineralized bone surface [97]. Thus, during bone resorption osteoclasts limited and integrins to interact with the extracellular matrix, in which the former bind to bone-enriched RGD-containing proteins, such as bone sialoprotein and osteopontin, whereas integrins demark to collagen fibrils [133, 134]. Despite these bindings, osteoclasts are highly motile even agile resorption and, as migrating cells, osteoclasts do non express cadherins. However, information technology has been demonstrated that cadherins provide intimate contact between 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 function of these cells, whereby signals induced by tissue deformation are generated and amplified [136]. It is still not articulate which integrins are involved, merely it has been suggested that and integrins are involved in osteocyte-os matrix interaction [137, 138]. These interactions occur between osteocyte body and the os matrix of the lacuna wall as well every bit between canalicular wall with the osteocyte processes [137].
Only a narrow pericellular infinite filled past a fluid separates the osteocyte cell body and processes from a mineralized bone matrix [58]. The space betwixt osteocyte cell body and the lacunar wall is approximately 0.v–ane.0μm wide, whereas the distance between the membranes of osteocyte processes and the canalicular wall varies from 50 to 100 nm [139]. The chemic limerick of the pericellular fluid has not been precisely divers. Nonetheless, a various array of macromolecules produced by osteocytes such as osteopontin, osteocalcin, dentin matrix protein, proteoglycans, and hyaluronic acrid is present [136, 140, 141].
The osteocyte and their processes are surrounded past a nonorganized pericellular matrix; fragile fibrous connections were observed within the canalicular network, termed "tethers" [139]. It has been suggested that perlecan is a possible chemical compound of these tethers [141]. Osteocyte processes can also attach straight by the "hillocks," which are protruding structures originating from the canalicular walls. These structures grade close contacts, possibly by means of -integrins, with the membrane of osteocyte processes [137, 142]. Thus, these structures seem to play a key part in the mechanosensitive function of osteocytes, by sensing the fluid flux movements along with the pericellular space, provoked by mechanical load forces [143]. In addition, the fluid flux movement is also essential for the bidirectional solute transport in the pericellular infinite, which influences osteocyte signaling pathways and advice amongst bone cells [144, 145].
2.7. Local and Systemic Factor That Regulate Bone Homeostasis
Bone remodeling is a highly complex bike that is achieved by the concerted actions of osteoblasts, osteocytes, osteoclasts, and os lining cells [3]. The formation, proliferation, differentiation, and activity of these cells are controlled past 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, i,25-dihydroxyvitamin Dthree (calcitriol), glucocorticoids, androgens, and estrogens [sixteen, 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 principal crusade of bone loss and osteoporosis [16]. The mechanisms by which estrogen act on bone tissue are not completely understood. Yet, several studies have 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 as induces osteoclast apoptosis [16, 76, 104, 154]. Information technology has been suggested that estrogen decreases osteoclast germination 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 [xix, 155–159]. In addition, estrogen inhibits osteoclast formation by reducing the levels of other osteoclastogenic cytokines such as IL-1, IL-6, IL-11, TNF-α, TNF-β, and Yard-CSF [160, 161].
Estrogen acts directly on bone cells by its estrogen receptors α and β present on these cells [162]. Moreover, it has been shown that osteoclast is a direct target for estrogen [163, 164]. Accordingly, immunoexpression of estrogen receptor β has been demonstrated in alveolar bone cells of estradiol-treated female person rats. Moreover, the enhanced immunoexpression observed in TUNEL-positive osteoclasts indicates that estrogen participates in the control of osteoclast life span direct past estrogen receptors [163]. These findings demonstrate the importance of estrogen for the maintenance of bone homeostasis.
2.eight. Bone Remodeling Procedure
The os remodeling cycle takes place within bone cavities that need to exist remodeled [165]. In these cavities, there is the formation of temporary anatomical structures called basic multicellular units (BMUs), which are comprised of a grouping of osteoclasts ahead forming the cutting cone and a group of osteoblasts behind forming the closing cone, associated with blood vessels and the peripheral innervation [11, 166]. It has been suggested that BMU is covered by a canopy of cells (perhaps bone lining cells) that form the bone remodeling compartment (BRC) [13]. The BRC seems to be connected to bone lining cells on bone surface, which in plow are in advice with osteocytes enclosed inside the bone matrix [13, 14].
The bone remodeling cycle begins with an initiation stage, which consists of bone resorption past osteoclasts, followed by a phase of bone formation by osteoblasts simply between these 2 phases, there is a transition (or reversal) phase. The cycle is completed past coordinated actions of osteocytes and bone lining cells [10, 11]. In the initiation phase, under the activeness of osteoclastogenic factors including RANKL and M-CSF, hematopoietic stem cells are recruited to specific os surface areas and differentiate into mature osteoclasts that initiate os resorption [167, 168].
It is known that during bone remodeling wheel, in that location are direct and indirect communications among bone cells in a process called coupling mechanism, which include soluble coupling factors stored in bone matrix that would be released after osteoclast bone resorption [169]. For instance, factors such every bit insulin-similar growth factors (IGFs), transforming growth factor β (TGF-β), BMPs, FGF, and platelet-derived growth factor (PDGF) seem to human activity as coupling factors, since they are stored in bone matrix and released during bone resorption [170]. This idea is supported past genetic studies in humans and mice too as by pharmacological studies [105, 171].
Recently, it has been suggested that another category of molecules called semaphorins is involved in the bone cell communication during os remodeling [146]. During the initial phase, osteoblast differentiation and activity must be inhibited, in order to completely remove the damaged or aged bone. The osteoclasts express a factor called semaphorin4D (Sema4D) that inhibits bone formation during bone resorption [172]. Semaphorins comprise a large family of glycoproteins which are non only membrane-jump only also exist as soluble forms that are found in a wide range of tissues and shown to be involved in diverse biological processes such as immune 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) nowadays in osteoblasts and inhibits IGF-1 pathway, essential for osteoblast differentiation [172], suggesting that osteoclasts suppress bone formation by expressing Sema4D. Conversely, another member of semaphorin family (Sema3A) has been found in osteoblasts and is considered an inhibitor of osteoclastogenesis [177]. Thus, during the os remodeling wheel, osteoclasts inhibit bone formation by expressing Sema4D, in order to initiate os resorption, whereas osteoblasts express Sema3A that suppresses bone resorption, prior to bone germination [146] (Figure five).
Recent studies besides suggest the existence of other factors involved in the coupling mechanism during the bone remodeling cycle. 1 of these factors is ephrinB2, a membrane-bound 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 reverse signaling (ephrinB4/ephrinB2) inhibits osteoclastogenesis [178] (Figure v). These findings advise that ephrinB2/ephrinB4 pathway may be involved in the catastrophe of bone resorption and induces osteoblast differentiation in the transition phase [178].
In addition, it has been shown that ephrinB2 is also expressed in osteoblasts [179]. Furthermore, mature osteoclasts secrete a number of factors that stimulate osteoblast differentiation such as the secreted signaling molecules Wnt10b, BMP6, and the signaling sphingolipid, sphingosine-one-phosphate [180]. These findings suggest a highly complex mechanism of ephrins and the involvement of other factors in osteoclast/osteoblast communication during the bone remodeling cycle. On the other mitt, 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 information technology is all the same controversial.
Besides osteoclasts and osteoblasts, information technology has been demonstrated that osteocytes play key roles during the os remodeling cycle [eight]. In fact, under the influence of several factors, the osteocytes act as orchestrators of the bone remodeling procedure, 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 equally PGE2, 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-1, which are inhibitors of osteoblast activity [185–188], also as specific factors that stimulate local osteoclastogenesis [189]. Sclerostin is a product of the SOST cistron and is known to be a negative regulator of os formation, by antagonizing in osteoblasts the actions of Lrp5, a key receptor of the Wnt/β-catenin signaling pathway [63].
Osteocyte apoptosis has been shown to act as a chemotactic betoken for local osteoclast recruitment [70, 150, 152, 190, 191]. Accordingly, information technology 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 4(d)). Moreover, it is reported that the osteoclastogenic factors is also produced by viable osteocytes nearby the dying osteocytes [193]. There is evidence that osteocytes act every bit the main source of RANKL to promote osteoclastogenesis [167, 168], although this factor has besides been demonstrated to be produced by other cell types such as stromal cells [194], osteoblasts, and fibroblasts [88, 89].
Thus, at that place are nevertheless uncertainties about the precise osteoclastogenesis-stimulating factors produced past osteocytes. Recent reviews have focused on some molecules that may be candidates for signaling between osteocyte apoptosis and osteoclastogenesis [72, 73]. For instance, in bones subjected to fatigue loading, viable osteocytes nigh 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 deed equally the main source of RANKL to promote osteoclastogenesis [166, 167]. In addition, 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]. Loftier mobility group box protein 1 (HMGB1) [198–200] and G-CSF [201] have also been suggested to be produced by osteocytes that stimulate osteoclast recruitment during bone remodeling [72, 73]. Thus, future studies are required to address this upshot.
ii.9. Endocrine Functions of Os Tissue
The classical functions of bone tissue, besides locomotion, include support and protection of soft tissues, calcium, and phosphate storage and harboring of bone marrow. Additionally, recent studies have focused on the bone endocrine functions which are able to bear on other organs [202]. For example, osteocalcin produced by osteoblasts has been shown to act in other organs [203]. Osteocalcin can exist found in ii dissimilar forms: carboxylated and undercarboxylated. The carboxylated form has high affinity to the hydroxyapatite crystals, remaining into bone matrix during its mineralization. The undercarboxylated form shows lower affinity to minerals, due to acidification of bone matrix during osteoclast bone resorption, and and so it is ferried by the bloodstream, reaching other organs [204, 205]. It has been shown that the undercarboxylated osteocalcin has some effects in pancreas, adipose tissue, testis, and the nervous system. In the pancreas, osteocalcin acts as a positive regulator of pancreatic insulin secretion and sensitivity as well as for the proliferation of pancreatic β-cells [110]. In the adipose tissue, osteocalcin stimulates adiponectin cistron expression that in plough enhances insulin sensitivity [204]. In the testis, osteocalcin can bind to a specific receptor in Leydig cells and enhances testosterone synthesis and, consequently, increases fertility [206]. Osteocalcin as well stimulates the synthesis of monoamine neurotransmitters in the hippocampus and inhibits gamma-aminobutyric acrid (GABA) synthesis, improving learning and memory skills [207].
Another endocrine part of bone tissue is promoted by osteocytes. These cells are able to regulate phosphate metabolism past the production of FGF23, which acts on other organs including parathyroid gland and kidneys to reduce the circulating levels of phosphates [208, 209]. Osteocytes also human activity on the immune organization past modifying the microenvironment in chief lymphoid organs and thereby influencing lymphopoiesis [210]. Non just osteocyte simply also osteoblast and osteoclast activities are known to influence the allowed organization, mainly upon bone inflammatory destruction. Indeed, the discovery of communication interplay between skeletal and immune systems led to a new bailiwick called osteoimmunology [211].
three. Conclusions
The knowledge of the structural, molecular, and functional biology of bone is essential for the better comprehension of this tissue as a multicellular unit and a dynamic construction that can also act equally an endocrine tissue, a function still poorly understood. In vitro and in vivo studies have demonstrated that bone cells reply to unlike factors and molecules, contributing to the better understanding of bone cells plasticity. Additionally, os matrix integrins-dependent bone cells interactions are essential for bone formation and resorption. Studies have addressed the importance of the lacunocanalicular system and the pericellular fluid, by which osteocytes deed every bit mechanosensors, for the adaptation of bone to mechanical forces. Hormones, cytokines, and factors that regulate os cells activeness, such as sclerostin, ephrinB2, and semaphoring, accept played a significant role in the bone histophysiology under normal and pathological conditions. Thus, such deeper understanding of the dynamic nature of os tissue will certainly help to manage new therapeutic approaches to bone diseases.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this newspaper.
Acknowledgments
This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-2010/10391-9; 2022/19428-eight, and 2022/22666-8), Conselho Nacional de Desenvolvimento Científico eastward Tecnológico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.
Copyright
Copyright © 2022 Rinaldo Florencio-Silva et al. This is an open access commodity distributed under the Creative Commons Attribution License, which permits unrestricted employ, distribution, and reproduction in whatsoever medium, provided the original work is properly cited.
Source: https://www.hindawi.com/journals/bmri/2015/421746/
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