The role of physical forces in osteoclastogenesis

Abstract

The movements of life at every level from organs, tissues, cells to sub‐cells, are all conducted in certain physical environments. In the human body, skeletal tissue among all connective tissues is influenced the most by physical forces. Studying the biological behavior of bone cells under different physical environments is helpful in further understanding bone homeostasis and metabolism. Among all bone cells, osteoclast (OC) and OC steered bone remodeling is one of the key points in bone metabolism. In the past few decades, people's understanding of OC was mostly limited to its involvement of bone resorption under physiological and pathological conditions. However, more and more studies started to focus on how physical forces affect the formation and differentiation of OC. This review tries to illustrate the knowledge up to date about how osteoclastogenesis is regulated by physical forces through direct and indirect ways, including fluid shear force, compressive force, and microgravity. The direct way describes the straightforward effects produced by different forces in osteoclastogenesis, whereas the indirect way describes the effects of different forces in osteoclastogenesis through regulation of other bone cells when a certain force is applied. Molecular mechanisms were analyzed and reviewed in both direct and indirect regulation by different forces. Finally, we discussed the status quo and tendency of related research, as well as other unresolved issues, and some future prospects.

In this review, we summarized the influence of different physical forces namely fluid shear stress (FSF), compressive force (CF), and microgravity, respectively in osteoclastogenesis both directly and indirectly.

1. INTRODUCTION

All cells are subjected to physical forces throughout their lifespan. Cells sense physical forces by surface adhesion receptors, which trigger signal transmission of adhesion molecules and rearrangement of cytoskeleton to react to the applied forces (DeMali, Sun, & Bui, 2014). The ligand‐adhesion molecules‐cytoskeleton pathway is thought to be another way to sense and transduce extracellular signals. Integrin as a typical adhesion molecule is demonstrated to withstand force exertion and transmit mechanical force stimuli to the cell interior by recruiting large number of cytoskeletal components and signal protein to form focal adhesion, which sense and response to force applied to integrins on the cell surface (DeMali et al., 2014; Roca‐Cusachs, Gauthier, Del Rio, & Sheetz, 2009). Unlike integrins, cadherins were recently considered to be mechanoresponsive as direct evidence showed that cells reinforce and stabilize cell–cell adhesions when twisting forces were applied to E‐cadherin (Watanabe, Hosoya, & Yonemura, 2007).

More and more studies are discussing the effects of physical force on bone metabolism. There is a complex interaction between bone tissue and physical force. Bone tissue must be loaded with the mechanical stress over a physiological magnitude to maintain the balance of bone remodeling and the bone mass (Ehrlich & Lanyon, 2002). Once this process is in chaos, the process of bone remodeling will be out of balance. Space traveling or limb disuse, for example, when physiological magnitude mechanical loading is lost, the decrease of bone mineralization will lead to the appearance of osteoporosis and bone loss. When bone tissue is subjected to a moderate mechanical loading, such as professional athletes, there will be a significant increasing of bone mineralization and new bone formation in bone tissue, and bone mass and bone density also increase, respectively (Fitts, Riley, & Widrick, 2001).

Osteoclasts (OC) are multinucleated cells derived from hematopoietic stem cells, which have a unique ability to resorb bone in both physiological and pathological conditions (Suda, Takahashi, & Martin, 1992). OCs are differentiated from cells of monocyte/macrophage lineage, with stimulation of two indispensable factors. The first is receptor activator of NF‐кB ligand (RANKL)(Anderson et al., 1997), the primary factor of OC differentiation, driving differentiation of OC precursors into mature OC through regulating gene expression by activating its cognate receptor, RANK (Anderson et al., 1997). The second factor is monocyte/macrophage colony stimulating factor (M‐CSF), which participates in the proliferation, survival, and differentiation of OC precursors in the early stage of osteoclastogenesis (Kodama, Nose, Niida, & Yamasaki, 1991). Osteopetrotic mice lack of M‐CSF display a remarkable deficiency in osteoclastic development (Wiktor‐Jedrzejczak et al., 1990). Besides, tumor necrosis factor alpha (TNF‐α) has also been reported to have the ability to induce OC recruitment (Wong et al., 2008), which may be the main cause of rheumatoid arthritis (Redlich et al., 2002), postmenopausal osteoporosis (Kimble, Srivastava, Ross, Matayoshi, & Pacifici, 1996). Bone remodeling is a physiological process which old bone is replaced by new bone, osteoblasts and OC are two main participants in the process of bone remodeling (Feng & Teitelbaum, 2013). Among them, osteoclastogenesis marked the beginning of each bone remodeling cycle. Therefore, OC, as well as osteoclastogenesis, is one of the key points in bone metabolism. Both bone remodeling and osteoclastogenesis occur within the bone marrow, except in certain pathological bone diseases. For instance, when osteoclastogenesis is excessively activated such as rheumatoid arthritis (Soysa, Alles, Aoki, & Ohya, 2012), postmenopausal osteoporosis (Raisz, 2005; Riggs, Khosla, & Melton, 1998), and breast cancers (Weilbaecher, Guise, & McCauley, 2011), where accelerated osteoclastogenesis takes place at a disease site outside the marrow cavity, thus resulting in abnormal bone resorption. Oppositely, when the activity of OC is oversuppressed, there will be diseases with increased bone mass such as osteopetrosis, also named Albers‐Schonberg disease, which is characterized by increased bone density due to defective bone resorption by OC (Zustin et al., 2018).

The role of physical forces in osteoblast, osteocyte, chondrocyte, and some other bone cells have already been extensively studied and reviewed previously (Dillaman, Roer, & Gay, 1991; Pan et al., 2010). However, as the only bone resorbing cell type, OC and the influence of physical forces in osteoclastogenesis are less studied and underestimated as we consider. Up to now, no review article has been reported summarizing the relationship between physical forces and osteoclastogenesis. In this review, we mainly focused on how the three physical forces, fluid shear stress (FSF), compressive force (CF), and microgravity (MG) affect osteoclastogenesis and the function of OC in bone remodeling through direct and indirect ways, then discussed which role physical force may play in certain pathological conditions.

2. DIRECT EFFECTS OF PHYSICAL FORCES IN OSTEOCLASTOGENESIS

OC and preosteoclast (POC) express RANK and M‐CSFR on their surface, but both of them do not secrete ligands of these two receptors. Therefore, there is no participation of the RANKL/osteoprotegerin (OPG) axis in the direct effects of physical force on osteoclastogenesis. In OC, signals of physical forces are received and transduce mostly by integrin (especially alpha v beta 3), which lead to an increase of intracellular calcium levels and cytosolic pH. Phospholipid metabolism is then changed and gene expression, especially OC differentiation‐related messenger RNA (mRNA) was altered, thereby macroscopically affecting the number and differentiation state of OC (Duong & Rodan, 1998). Physical forces also promote OC to release paracrine factors by molecular transportation, which affects the entire process of bone remodeling.

2.1. The influence of fluid shear force on osteoclastogenesis

Interstitial fluid (ISF) is the main component of body mass (up to 20%) and is distributed throughout the extracellular matrix. Cells infiltrate in ISF and exchange material with it. ISF provides cells with nutrients and waste removal, which is a necessary condition for cell metabolism. In addition, ISF can also buffer and protect cells. In the flow of ISF, the frictional force generated between the liquid and the surface of the object (usually the cell surface) is the shear force. In general, fluid shear force refers to the friction between the fluid flow and the solid boundary.

OC under FSF simulation shows obviously morphological changes including bigger volume and more number of microfilaments (O.H. Zhang et al., 2006), as well as significantly increasing of both number and area of bone resorption lacunas produced by OC (Oest, Miller, & Howard, 2014; Y. Liu et al., 2007). Calcium oscillation is closely related to the differentiation stages of OC, supported by the fact that the ability of calcium oscillation of OC at early differentiation is stronger than that at late differentiation (Sakai et al., 2010). FSS‐induced calcium oscillation occurred in small‐size OC, then the increase of intracellular calcium concentration activates calcineurin, which further leads to the activation of the nuclear factor of activated T‐cells, cytoplasmic 1 (NFATc1). NFATc1 upregulates the expression of tartrate‐resistant acid phosphatase (TRAP), cathepsin K, and β3 integrin; therefore, osteoclastogenesis is enhanced (P. Li et al., 2012; Negishi‐Koga & Takayanagi, 2009). Apart from this, FSF stimulates nitric oxide (NO), prostaglandin E2 (PGE2), and prostaglandin 2 (PGI2) production whereas induces osteoclastogenesis in bone marrow derived‐OC precursors (McAllister, Du, & Frangos, 2000), which support the hypothesis that OC may also be mechanosensitive like osteoblast and osteocyte (Rubin et al., 1997). One study also showed that FSF increases ATP6V1a and TCIRG1 mRNA expression, ATP6V1a and TCIRG1 are two crucial subunits of the vacuolar H⁺‐ATPase gene, which suggest that FSF stimulation may have a corresponding effect on the transmembrane transport of OC, even join the metabolic process (Guo et al., 2010).

2.2. The influence of CF in osteoclastogenesis

CF refers to the force that resists the compression of an object in the definition of physics. CF is an essential factor participated in homeostasis and physiological responses in human bodies. In skeletal tissue, the adjustment and maintenance of bone mass used to depend on the mechanical force received by the bone itself especially CF, which is also closely related to osteoblast and OC. Optimal CF increases bone density, which is a key factor to promote bone formation and reconstruction in bone remodeling such as fracture repair, orthodontic tooth movement, and distraction osteogenesis (Huang & Zeng, 2007; Hughes‐Fulford, 2004; Ilizarov, 1989).

It has been reported that CF accelerates osteoclastogenesis by upregulating expression of osteoclastogenesis‐associated genes such as NFATc1, TRAP, RANK, DC‐stamp, and OC‐stamp (Hayakawa et al., 2015); the first three are associated with OC differentiation, the rest two are related to cell fusion. A recent study shows a continuous application of CF promotes the fusion of RAW264.7 cells by upregulating expression of RANK and downregulating LGR4 (Matsuike et al., 2018). Another study displayed an inhibitory effect of CF removal on osteoclastic formation supported by inhibition of the expression of osteoclastogenesis‐related genes (Ikeda et al., 2016). Osteoclastogenesis‐related genes such as NFATc1 and calcitonin receptor (CTR) show high expression in POC under CF, which means CF may induce the early stage of osteoclastogenesis (Hou et al., 2014); in contrast, osteoblast precursor under CF shows low expression in osteoblastogenesis‐related genes such as Runx2 and Sp7, which means that CF inhibits the early stage of osteoblastogenesis to some extent (Hou et al., 2014). On the basis of the above findings, CF has different effects in the precursors of OC and osteoblast; and participates in the entire bone remodeling process by pulling the balance to improvement of osteoclastic function and reduction of osteoblastic function in a magnitude manner. In addition, both CF stimulation and TNF‐α promote osteoclastogenesis (Hayakawa et al., 2015; Kwak et al., 2005). CF also accelerated TNF‐α‐induced osteoclastogenesis; and this was inhibited either by anti‐TNF‐α or anti‐TNF‐α receptor but not by OPG³⁵. A report also showed that suture compression force promotes osteoclastogenesis by enhancing mRNA expression of matrix metalloproteinase (MMP)‐1 and MMP‐13, which lead to an increase in bone resorption, and a decrease in bone density and formation adjacent area to the suture (Y. Liu, Song, Sun, Yu, & Liu, 2012).

2.3. The influence of MG in osteoclastogenesis

It is considered that gravity plays an important role in bone remodeling (Porazinski et al., 2015). Space traveling can cause both long‐term and short‐term bone health problems (Grimm et al., 2016). MG plays the most important role in this process. Long‐term spaceflights can significantly affect the health of human in space due to MG (Grenon, Saary, Gray, Vanderploeg, & Hughes‐Fulford, 2012; Sides et al., 2005). Space motion sickness is very common, orthostatic intolerance and reduction of motor ability also appeared after flight, and one of the main reasons is the skeleton system is influenced by MG (Grenon et al., 2012; Sides et al., 2005). Because of the disappearance of gravity, muscles lose both mass and strength and the bone starts to demineralize, which cause alterations of bone mineral density and eventually result in osteoporosis, which is called disused bone loss (Cavanagh, Licata, & Rice, 2005; Fitts et al., 2001). Moreover, bone resorption due to space flight increases the risk of renal stones and the amount of urinary calcium (Smith et al., 2015). Thus, it can be seen MG has an important influence on the skeleton system, and indirectly affects other organs and systems of the body.

Medaka fish was once considered to be a classical animal model to investigate how MG affects bone remodeling. Decades ago, a five‐days spaceflight found an increase in bone resorption by OC as well as a decrease in osteoblast cellular integrity, with a 1–2% decrease in bone mass per month during space flight, especially significant in bone mass of the weight‐bearing bones, and it is found that the physiological function of medaka fish has undergone a series of impairment under continuously MG, which characterized by an increase in the number of OC and the activation of osteoclastic function (Carmeliet, Nys, & Bouillon, 1997; Chatani et al., 2015; Tilton, Degioanni, & Schneider, 1980). Recent years, it is confirmed that Wnt signaling pathway participated in disused bone loss in humans (Frings‐Meuthen et al., 2013). Studies have already found that whereas MG increases osteoclastogenesis directly, it also inhibits osteoblastogenesis (Saxena, Pan, & McDonald, 2007; Tamma et al., 2009).

During the whole process of bone remodeling, there exists a close coupling between bone resorption and bone formation to guarantee no change in bone mass after each remodeling cycle, and OC plays an important role in this whole process (Z. Li, Kong, & Qi, 2006). The bone loss promoted by MG during space flight is due to the uncoupling of bone resorption and bone formation induced by changes of bone cells (Carmeliet et al., 1997; Hughes‐Fulford & Lewis, 1996; Monticone, Liu, Pujic, & Cancedda, 2010). Osteoclastogenesis is improved under MG, characterized by an increase in both number and activity (Vico, Bourrin, Genty, Palle, & Alexandre, 1993). This may be related to the activation of osteoclastogenesis‐related signaling molecules such as extracellular regulated protein kinases (ERK), p38, and NFATc1, which can promote RANKL mediated osteoclastogenesis, thus lead to an increase in bone resorption (Hu et al., 2014; Saxena, Pan, Dohm, & McDonald, 2011; Yuge et al., 2003).

3. INDIRECT EFFECTS OF PHYSICAL FORCE IN OSTEOCLASTOGENESIS

Physical forces could affect bone cells and some other cells (such as human periodontal ligament [PDL] cells, synovial cells, etc.). These cells react differently to external stimuli of physical forces after the force application by releasing signal molecules through molecular transportation. In the indirect regulation of physical forces in osteoclastogenesis, signals mostly received and transduced by RANK to regulate the activity and function of OC mainly rely on the participation of RANKL/OPG axis.

3.1. Osteoblast mediated effects

Osteoblasts are not located in narrow lacuna and surrounded by mineralized bone matrix like osteocytes. Because of the deficient knowledge about the physical features of the osteoids, estimation of FSF values become more complicated. Unlike osteocytes, osteoblasts might be more likely to be affected by low FSF, for osteoblast is not as embedded in the bone matrix as osteocytes (Wittkowske, Reilly, Lacroix, & Perrault, 2016).

The process of FSF indirectly affects osteoclastogenesis through osteoblast can be divided into four steps: (a) As mechanosensitive cells, osteoblasts receive stimulation from FSF mostly by integrin on the cell surface (Kamel, Picconi, Lara‐Castillo, & Johnson, 2010); (b) Activation of a series of downstream signaling pathways such as the changes of PGE2 and calcium concentration (Hung, Pollack, Reilly, & Brighton, 1995; Liegibel et al., 2004; You et al., 2001); (c) The changes of PGE2 concentration induce β‐catenin nuclear translocation, which can activate osteoblastogenesis‐related genes such as Runx2, ALP, and collagen I, and so forth (Bakker, Soejima, Klein‐Nulend & Burger, 2001; Kamel et al., 2010; Klein‐Nulend, Burger, Semeins, Raisz, & Pilbeam, 1997; Reich & Frangos, 1991); (d) osteoblasts release factors such as RANKL both in the early stage and late stage of osteoblastogenesis, which promote osteoclastogenesis. Besides, FSF rapidly increases intracellular calcium (Hung et al., 1995; You et al., 2001), nitric oxide (Johnson, McAllister, & Frangos, 1996; Owan et al., 1997), inositol trisphosphate (Reich & Frangos, 1991), adenosine triphosphate (ATP; Genetos, Geist, Liu, Donahue, & Duncan, 2005), and PGE2 (Bakker et al., 2001; Klein‐Nulend et al., 1997; Reich & Frangos, 1991) levels in osteoblast cultures. Fluid flow has also been shown to regulate expression of osteoblast genes for osteopontin (OPN; Owan et al., 1997; You et al., 2001), cyclooxygenase‐2 (COX‐2), and c‐FOS (Pavalko et al., 1998), but also genes related to matrix metabolism such as collagen I (Myers, Rattner, Shrive, & Hart, 2007).

Some complicated regulations that FSF influenced osteoclastogenesis through osteoblast recently have been clarified. Stepwise fluid shear force differently regulated and control osteoblast functions, thus further affecting osteoclastogenesis. Compared with the control group, stepwise increasing FSF will apparently reduce the expression of RANKL in osteoblast and increased OPG. In contrast, stepwise decreasing FSF apparently induces the expression of RANKL and reduced OPG in osteoblast, which can be said that the increasing FSF restrains the indirect way by reducing the secretion of RANKL and increasing OPG (Pan et al., 2011). In addition, unconventional FSF study has also been reported. A study has reported that oscillatory fluid flow‐induced shear stress decreases the RANKL expression and increase the OPG expression in bone stromal cells (Kim, You, Yellowley, & Jacobs, 2006), production of OPG leads to an inhibition of osteoclastogenesis. Similarly, Rucci, Rufo, Alamanou, and Teti (2007) reported that modeled MG stimulates osteoclastogenesis indirectly by an increase in RANKL/OPG ration osteoblasts.

After it is discovered that CF promotes RANKL and reduce OPG production through PGE2 pathway in osteoblast which promotes osteoclastogenesis (Kanzaki, Chiba, Shimizu, & Mitani, 2001; Sanuki et al., 2010; Wise & King, 2008), studies reported that Caspase‐3 protein activity is elevated in osteoblast in the presence of CF stimulation. Caspase‐3 plays an irreplaceable role in the process of cell apoptosis, which directly leads to the apoptosis of osteoblast and inhibits the osteogenesis effect. Studies reported that CF regulate osteoblast apoptosis via c‐Jun N‐terminal kinase (JNK) mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K)/Akt signaling pathways, large‐magnitude CF induces osteoblast apoptosis, small‐magnitude CF inhibits osteoblast apoptosis conversely, both of them achieve their effects by regulating Bcl‐2, Bax, Bad, and Caspase‐3 (Song et al., 2016). A previous study found osteoblastic differentiation has a maximum improvement when the compression force around 1.0 g/cm² (Yanagisawa et al., 2008). Another study reported that osteoblastic differentiation was induced when CF was elevated from 2.0 to 4.0 g/cm² (Tripuwabhrut, Mustafa, Gjerde, Brudvik, & Mustafa, 2013). All the above are discussed the effects of CF in osteoblast differentiation and osteoblast‐regulated osteoclastic differentiation in a magnitude‐dependent manner, the different magnitude can achieve different effects (Shen et al., 2017). Furthermore, CF induces OS differentiation by increasing expression of COX‐2 gene in osteoblasts, which significantly lead a high production of PGE2 (Sanuki et al., 2010). Cyclic CF also upregulates mRNA level of scinderins in osteoblast, which can support osteoclastogenesis through NF‐κB, p‐Smad1/5/8, and MAPK P38 signaling pathways accompanied by increased mRNA expression of NFATc1 and c‐Fos (Wang et al., 2017).

3.2. Osteocyte mediated effects

Osteocytes are the most abundant cells located in bone tissue and constitute the main part of bone tissue together with bone matrix. The osteocytes embedded in the bone matrix and form cell–cell communication with osteoblasts and OC by a large number of gap junctions located at the cells body and their processes. At present, it is considered that osteocytes transmit biological signals to osteoblasts or OC by secreting small molecules under physical force stimulation. In addition to the entire extracellular matrix, the ISF also fills the lacunar‐canalicular system, which is a kind of channel construction surrounding osteocytes. Because of the small size of the channel, the ISF is squeezed through the narrow channel, generating a shear stress comparable to the shear stress of the vessel wall, that is fluid shear force (Cowin & Cardoso, 2015). Besides, it has proved that mechanically sensitive cells (especially osteocytes) are stimulated by FSF whereas the bone receives physical force (Dillaman et al., 1991).

Osteocytes communicate with Iand OC osteoblasts mainly through gap junctions, also known as connexins (Civitelli et al., 1993). Connexin 43 is the most common connexin on the surface of bone cells including osteocytes, osteoblasts, and OC (Civitelli et al., 1993; Ilvesaro, Vaananen, & Tuukkanen, 2000; Yellowley, Li, Zhou, Jacobs, & Donahue, 2000). Studies demonstrated that connexins allow small molecules to pass through, including Ca²⁺ and PGE2, to make sure that osteocytes respond to external stimulation of mechanical stress and send information to other bone cells (X. Li et al., 2013). It has been clarified that FSF promote osteocytes to release several physiological messengers in vitro including Ca²⁺, ATP, NO, and PGE2 (Genetos et al., 2005; Jing et al., 2013; Kamel et al., 2010; Klein‐Nulend et al., 1997; Lu, Huo, Park, & Guo, 2012). And all these factors are demonstrated to have a significant effect on bone remodeling process. For instance, NO is a short‐acting factor in bone metabolism, which promotes bone formation and inhibits bone resorption (Bakker et al., 2001).

FSF also affects the production of RANKL and OPG in osteocytes. J. Li, Rose, Frances, Sun, and You, (2012) has demonstrated that steady or oscillatory flow can downregulate RANKL expression and upregulate the expression of OPG in flow chamber experiments. Some ways which physical forces influenced osteoclastogenesis indirectly by osteocytes recently have been reported. Fahlgren, Bratengeier, Semeins, Klein‐Nulend, and Bakker (2017) lately found that supraphysiological loading enhance expression of membrane‐bound RANKL of osteocytes and promote OS differentiation by intercellular communication between osteocytes and bone marrow cells, and supraphysiological loading did not change mRNA expression of RANKL and OPG in the stage of OS differentiation, which suggests that there is no participation of RANKL/OPG axis this process. A large number of OS was observed in the coculture system of osteocytes and bone stromal cells, the number of OS was immediately reduced whereas FSF was applied and slowly increased with the prolonged applying FSF time. The results showed that the OPG expression decreased and the RANKL expression increased in osteocytes after FSF stimulation. FSF can also influence osteoclastogenesis indirectly through regulation of interleukin‐17A (IL‐17A) secretion. IL‐17A upregulates the expressions of osteoclastogenic factors in osteocyte whereas the stimulation of fluid shear force downregulates expressions of osteoclatogenic factors in osteocyte, and the effects of IL‐17A was inhibited by stimulation of FSF (Liao et al., 2017), Which means FSF inhibits osteoclastogenesis indirectly by suppressing the promotive effects of IL‐17A in osteocytes. It is previously demonstrated that osteocytes produce OPN as an early response to CF, which induce bone resorption (Terai et al., 1999). OPN is considered to play an important role in bone formation, and was found have an ability to promote and support the attachment between OS and bone marrow (De Fusco et al., 2017; Gundberg, 2003). Expression of OPN mRNA was detected in compressed osteocyte, therefore compressed osteocytes may play a critical role in inducing osteoclastic bone resorption activated by physical forces (Takano‐Yamamoto, 2014). Also, expression of CCN‐2 upregulated by compression on osteocyte induces osteoclastic bone resorption and osteocyte apoptosis through MAPKs (Takano‐Yamamoto, 2014).

3.3. Other bone cells

PDL cells are the main cells of periodontal tissue which play an important role in the development, function, and regeneration of periodontal supporting tissue. PDL cells can differentiate into fibroblasts, osteoblasts, and cementoblasts to synthesize extracellular matrix in cementum and periodontal tissue (Lekic & McCulloch, 1996). Study also shows that PDL cells under physical force has a significant promotive effect in osteoclastogenesis, because PDL cells stimulated by CF express a high level of RANKL and a lower level of OPG (Nakao et al., 2007; Yamaguchi, Aihara, Kojima, & Kasai, 2006), and enhanced RANKL expression and reduced OPG expression together in PDL cells may support OS formation in OS progenitors (D. Zhang, Yang, Li, & Fu, 2004; Hasegawa et al., 2002; Kanzaki et al., 2001; Yamaguchi et al., 2006). Another study also found that CF improves VEGF expression in PDL cells, significant bone resorption around the compression area was observed (Miyagawa, Chiba, Hayashi, & Igarashi, 2009). VEGF, which is known to support OS formation and increase OS differentiation through Flt‐1, is also proved to straightly induce OS bone resorption, and significant for recruitment of OC into developing long bones (Aldridge, Lennard, Williams, & Birch, 2005; Engsig et al., 2000; Nakagawa et al., 2000; Niida et al., 1999). Moreover, asporin produced in compressed PDL cells is also an activating factor for OC to induce bone resorption, which displayed a significantly decreasing in the bone mineralized area (Ueda et al., 2016). Besides, CF also induces OS formation via upregulating expression of RANKL on synovial cells, therefore compressed synovial cells induce OS formation, continuously CF stimulation may cause destruction in the synovial joint or other joints by activating osteoclastic bone resorption (Ichimiya et al., 2007).

4. CONCLUSION AND PERSPECTIVE

In this review, we summarized the influence of different physical forces namely FSF, CF, and MG, respectively in osteoclastogenesis both directly and indirectly (Figure 1 and Table 1). These findings proved that physical forces modulate some important factors in the processes of bone formation and bone resorption. In the past decades, various experimental equipment and models have been applied to explore how physical forces affect bone formation and bone resorption. These studies explained how bone cells respond to different kinds and magnitudes of physical forces.

Figure 1.

Direct and indirect effects of various physical forces on osteoclastogenesis. Direct effects: CF, FSF, and MG directly act on osteoclasts, promote osteoclastogenesis, and osteoclastic differentiation, which are mainly accomplished by integrin signaling pathways after stimulation of physical forces application. Indirect effects: CF, FSF act on osteoblasts and osteocytes, upregulate RANKL expression and downregulate OPG expression to promote oseteoclastogenesis. CF: compressive force; FSF: fluid shear stress; MG: microgravity; OPG: osteoprotegerin; RANKL: receptor activator of NF‐кB ligand [Color figure can be viewed at wileyonlinelibrary.com]

Table 1.

The effect of various physical forces on three bone cells

	Osteoclast
Force	Preosteoclast	Mature osteoclast	Osteoblast	Osteocyte
FSF	Promote the differentiation of POC by integrin, independent of RANKL/OPG axis	Increase in size; enhance bone resorption independent of RANKL/OPG axis	Induce OB to secrete a series of factors that induce OC differentiation	Promote osteocyte to secrete factors that induce OC differentiation; increasing RANKL and decreasing OPG
CF	Promote the differentiation of POC by integrin, independent of RANKL/OPG axis	Increase expression of osteoclastogenesis‐related genes expression such as NFATc1, TRAP, RANK, and so on.	Increase RANKL and decrease OPG; inhibit osteoblastogenesis; induce the apoptosis of OB by Caspase‐3; increasing COX‐2 to lead high PGE2	Support indirect way by increasing OPN and CCN‐2
MG	Increase osteoclastogenesis	Increase number and activity	Unknown	Unknown

Note. CF: compressive force; COX‐2: cyclooxygenase‐2; FSF: fluid shear stress; MG: microgravity; NFATc1: nuclear factor of activated T‐cells, cytoplasmic 1; OB: osteoblast; OC: osteoclast; OPG: osteoprotegerin; PGE2: prostaglandin E2; POC: preosteoclast; RANKL: receptor activator of NF‐кB ligand; TRAP: tartrate‐resistant acid phosphatase.

Overall, physical forces play crucial roles in regulating OS function in bone development and homeostasis both directly and indirectly. However, there are few studies on the direct effects of physical force on osteoclastogenesis, current studies are rather limited and further knowledge is to be explored to better understand the mechanisms of how physical forces affecting osteoclastogenesis and its participation in bone homeostasis.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.