INTRODUCTION:

The use of orthodontic appliances to correct malocclusion involves the process of alveolar bone remodeling. The process can be stimulated using a mechanical force obtained from the activation of appliance components applied to press the teeth and forwarded to the surrounding tooth tissues including gingiva, periodontal ligament and alveolar bone. Mechanical force causes the area around the teeth divided into two regions i.e. the compression area and tension area. In the compression area, the mechanical force will stimulate the osteoclast to perform alveolar bone resorption. On the other hand, in the tension area a new alveolar bone formation will be performed by osteoblasts¹.

Osteoclasts are giant cells with many cell nuclei found only in bone. Osteoclasts are originated from hematopoietic precursor cells, and are monocytes/macrophage lineages that will specifically form mononuclear preosteoclasts that will subsequently become multinucleated osteoclasts.

Osteoblasts are originated from undifferentiated MSCs. The osteoprogenitor cells develop into preosteoblasts, and subsequently become osteoblasts that have the ability to conduct mineralization and bone calcification. When bone formation process has been completed, the osteoblasts differentiate into osteocytes buried in bone². Osteoclast precursor cells are identified as granulocyte macrophage colony forming units (CFU-GM), which develop into granulocytes, monocytes and osteoclasts CFU-GM derived cells differentiate into committed osteoclast precursors, which are postmitotic cells and combine to form multinucleated osteoclasts³. During the osteoclast differentiation process, the precursor cell expresses the c-Fms (M-CSF receptor) followed by RANK. M-CSF and RANKL produced by osteoblasts and play an important role in the osteoclast progenitors proliferation and differentiation⁴. Osteoblast is originated from Mesenchymal Stem Cells (MSC) in the bone marrow, differentiate into osteocytes and are immersed in calcified bone⁵. RANKL and RANK interactions will lead to osteoclast formation and differentiation stimulation through some osteoclastogenesis transcription factors activation⁶.

Intercellular communication in bone remodeling processes requires modulation and formation of MSC for osteoblasts, and hematopoietic stem cells (HSC) for osteoclasts. MSC is essential in improving bone and cartilage regeneration.^7,8 The optimal combination of MSCs with the right order improves the success of regeneration ^9,10,11. MSC culture expansion is needed to produce enough MSC and used as a framework for improving bone loss. Discerning selection of MSC sources will result in better quality of tissue repair¹². On the other hand, HSC formation and propagation are strongly influenced by osteoclastic activity. Activated osteoclast activity inhibited by molecular and cellular interactions may lead to inhibition of HSC colonization. In addition, HSC may decrease in number due to selective osteoblasts reduction due to an increase in osteoblasts number related with an enlarged HSC pool size¹³.

This study was aimed at explaining and understanding osteoclast and osteoblast stem cells in bone remodeling stimulated by the mechanical force of the orthodontic appliance.

Mesenchymal Stem Cells (MSC)

MSC is a multipotent stromal cell, can differentiate into several types of cells including chondrocytes, osteoblasts, myocytes, adipocytes and neurons. MSC has a small cell body with several long and thin cell extensions¹⁴. The cell body consists mostly of a round nucleus with a prominent nucleolus surrounded by flat scattered chromatin particles, thus it provides a clear appearance of the nucleus. Other parts of the cell body consist of small parts of the Golgi body, rough endoplasmic reticulum, mitochondria and polyribosome ¹⁵. MSC resides in several places^16,17i.e. developing tooth bud of the lower third molar, dentalpulp and gingiva^18,19,20, blood and umbilical cord tissue^21,22, amniotic fluid, and adipose tissue²³.

The International Society for Cellular Therapy (ISCT) has standards for the identification of MSC^24,25 as presented in following Table 1.

Table 1. Criteria for Identification of MSC ²⁴

1.	Adherence to plastic in standard culture conditions
2.	Phenotype	Positive (> 95 % +)	Negative (<2 % +)
		CD 105 CD 73 CD 90	CD 45 CD 34 CD 14 or CD 11b CD 79α or CD 19 HLA DR
3.	In vitro differentiation: osteoblast, chondroblast and adipocytes (demonstrated by staining of in vitro cel culture)

Description:

CD34 (cluster of differentiation 34/Hematopoietic progenitor cell antigen CD34); SCA-1 (Stem cells antigen-1); CD59 (MAC-inhibitory protein (MAC-IP)/membrane inhibitor of reactive lysis (MIRL)/ protectin); Thy1 (Thymocyte differentiation antigen 1); CD38 (cluster of differentiation 38/cyclic ADP ribose hydrolase); C-kit (Mast/stem cell growth factor receptor (SCFR)/proto-oncogene c-Kit/tyrosine-protein kinase Kit/CD117); lin (lineage marker)

Hematopoietic Stem Cells (HSC):

HSC is a blood cell that produces all other blood cells and is originated from mesoderm. They reside in a red bone marrow contained in the middle on most of the bones. HSC is also defined as a cell with long-term and short-term regeneration capacities and is committed to multipotent, oligopotent, and unipotent progenitors¹⁴. HSC itself is a cell with a number 1: 10,000 in myeloid tissue. HSC produces blood cells from myeloid strains (macrophages, monocytes, neutrophils, basophiles, eosinophils, erythrocytes, megakaryocytes or platelets and dentriticcells ) and lymphoid (B cells, T cells and natural killer cells)²⁶. HSC microscopically has images like lymphocytes, i.e. non-adherent, spherical, spherical nucleus and low cytoplasm-to-nucleus ratio. HSC, at baseline/primitive conditions, cannot be separated as a pure cell population, making it impossible to identify on a microscope²⁷. HSC is found in mature bone marrow, especially in the femur, pelvis and sternum. It is also found in small amounts of umbilical cord^21,22 and peripheral blood²⁷.

Some cell surface proteins in rats and humans can be used as markers for HSC identification when they are in undifferentiated state in vitro and in vivo¹⁷. When HSC begins to develop into cell lineages, these cell surface markers can no longer be used for identification²⁸. These cell surface markers can be seen in Table 2.

Table 2. Cell Surface Markers in HSC Rat and Human²⁸

Rat	Human
CD34^low/-	CD34⁺
SCA-1⁺	CD59⁺
Thy1^+/low	Thy1⁺
CD38⁺	CD38^low/-
C-kit⁺	C-kit^-/low
lin^-	lin^-

Description:

DISCUSSION:

The mechanical forces generated by orthodontic appliance activation imposed on teeth and periodontal tissues produce biophysical signals with different styles of force. Tension forces in alveolar bone and PDL have the ability to stimulate osteogenic gene expression required in the process of differentiating osteogenic progenitor cells becomes mature osteoblasts with osteoid precipitation occurring during mineralization. On the other hand, the compression forces on the PDL and alveolar bone stimulate RANK expression directly the action of IL-1β and prostaglandins, which initiate resorption by osteoclasts²⁹.

MSC Response to Mechanical force from Orthodontic Appliance:

The tension force on the MSC in the PDL will activate the signaling pathway mediated by the ERK protein kinase 1/2 (family of mitogen-activated protein kinase/MAPK molecules). The ERK 1/2 pathway activation causes the induction of the transcription factor Runx 2, which is an important regulator in osteogenic gene expression, triggering the osteogenic progenitor cells differentiation and maturation into osteoblasts, and then produce collagen type 1,alkaline phosphate and osteocalcin. In addition to the MAPK intracellular signaling pathway, c-JUN cascade N-terminal kinase (JNK) and p38 also play a role in osteoblasts^30,31.

In general, the mechanotransduction in MSC can be divided into several paths i.e. integral and Chaderin-mediated signaling focal adhesion (FA), signaling of soluble factors such as Wnt and TGF-β and Mechanosensitive Ion Channels (MIC). Several different signals include soluble-mediated factor transduction signal pathways, mechano-sensing cellular processes and unified mechano-transduction to activate intracellular intracellular signaling networks in an integrated and interactive manner regulating the fate of SC³².

The mechanotransduction system through integrin signaling is played by focal adhesion kinase (FAK) and kinases of the Src family like fyn. The main downstream signaling pathway that follows the FAK/Src initiation is path of Ras-Raf-MEK-ERK, but the molecular mechanism by which integrins regulate MAPK remains unclear. Some possible pathways are integrin-(FAK)/(fyn-Shc)-Grb2-SOS-Ras or through an EGF receptor. Translocation of ERK into the nucleus can regulate gene expression through activating some required transcription factor^33,34.

The other racial downstream path is the PI3k/Akt path, can be initiated via integrin signaling. The pathway of PI3k/Akt is known to be important for SC self-renewal and differentiation. Paling et al³⁵ reports that PI3k signaling is activated through LIF and needed to maintain SC self-renewal, and one of the downstream signaling goals for PI3k/Akt is Nanog³⁶.

RhoA is the main molecular regulator of actinous cytoskeleton pressure and focal adhesion (FA) formation, often referred to as upstream regulator integrin, by the action of the Rho-kinase effectors (ROCK). Signaling RhoA/ROCK also acts as a downstream signaling target mediated by the activated FAT³⁷. RhoA can be initiated by different cytokines and growth factors as well as biophysical signals from their cellular microenvironment. The functional role of RhoA /ROCK mediated by cytoskeleton contractility is required for lineage commitments from MSC. Activated RhoA triggers MSC osteogenesis through the regulation of Runx2 expression, when RhoA is inhibited causing MSC adipogenesis. In response to the activation of RhoA/ROCK signaling, an intact actin cytoskeleton structure is required for MSC differentiation in mechanoresponsiveness. RhoA/ROCK-mediated cytoskeletal contactivity may directly regulate multiple gene expression of the transcription factor (e.g. PPAR-γ and Sox-9) to affect differentiation of SC³⁸.

Dupont et al³⁹ explains that an alternative signaling pathway have an important role in determining the fate of SC is the Hippo pathway. The effector targets of this pathway are Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), and like β-catenin also translocates into the nucleus and regulates gene expression. The YAP/TAZ pathway is essential for responding to changes in substrate stiffness and cell shape. This pathway is also known to be important in the process of osteogenic differentiation of human bone marrow from MSC derivates, by removing obstacles from the YAP and TAZ pathways, and normally will trigger osteogenic differentiation process.

The second signaling of mechanotransduction is the soluble-mediated signaling, including Wnt, TGF-β and other factors. Signaling Wnt / β-catenin can regulate the decision of the fate of SC. Expression, nuclear translocation and β-catenin accumulation on the Wn canonical path are regulated by Dvl. Wnt and integrin signaling interactions occur through two distinct pathways: integrin-linked kinase (ILK) and FAK. ILK plays a role for stabilizing and/or stimulating nuclear accumulation of β-catenin, whereas other pathways, Grb2 integrate with integrin signaling via FAK by Wnt signaling through Dvl and jnk, where Dvl and Jnk are downstream kinases of Grb2 and stimulate β-catenin to the nucleus translocation. β-catenin translocation will subsequently activate the Runx2 gene. In addition to SC levels, Wnt signaling generated by biophysical signals can directly regulate osteoblasts. When mechanical forces are applied, Wnt signaling can decrease the expression of β-catenin even though it initially increases the β-catenin expression⁴⁰. Other researchers mentioned that the osteogenic differentiation process of MSC, played by the cooperation between canonical Wnt and BMP. BMP, specifically BMP-2 induces p300-mediated acetylation Runx2 which results in increased Runx2 capability. This shows that there is cooperation between BMP and canonical Wnt in regulating Runx2⁴¹.

TGF-β plays a major role in inhibiting cell proliferation, which is associated with maintaining SC in quiescent states⁴², and several other studies suggest that TGF-β plays an important role in maintaining pluripotency of SCs through Smad2/3 signaling⁴³. Besides playing an important role in signal transduction through the Smad2/3 signaling line, TGF-β can also activate other important signaling pathways e.g. PI3k, MAPK and Rho/ROCK⁴⁴. Signaling linkages between integrin and TGF-β can be explained that integrins can directly regulate TGF-β activation through cellular attraction given by actin cytoskeleton and G-protein coupled receptors (GPCR). But integrins can indirectly control the TGF-β pathway by activating the release of TGF-β from ECM when there is a mechanical force from outside the cell. TGF-β may regulate the actin cytoskeleton via the RhoA/ROCK pathways⁴⁵.

The third signaling of mechanotransduction is MIC-mediated signaling. MIC may be related to the extracellular matrix and/or cytoskeleton, as well as the relative changes of the pathway associated with the extracellular matrix or cytoskeleton as the pathway opening response. Thus, MIC is directly initiated by external forces or intracellular cytoskeleton contactivity⁴⁵. The main downstream effect of MIC activation is the change in cytoplasmic Ca2+ concentration corresponding to the size of the force. Some studies suggest that changes in Ca2+ concentrations observed in MSC act as indicators and regulators of MSC differentiation⁴⁶. Kim et al⁴⁷ mentioned that changes in Ca2+ concentrations indicate mechanical forces have the important role to directly regulate the fate of SC through modulating calcium signals.

HSC Response to Mechanical Force from Orthodontic Appliance:

In the opposite area i.e. the compression area, alveolar bone resorption processes require modulation of endosteal HSC nerve formation. Regulation of alveolar bone resorption is preceded by the recruitment of osteoclast precursor cells, all of which are mediated by osteoblastic lineage cells. This cooperation requires cellular contact, cytokine production and the formation of factor coupling during the process⁴⁸. Osteoblasts and other mesenchymal cells e.g. perivascular primitive mesenchymal cells, provide a niche in which HSC is exposed to molecular signals like cytokines, chemokines and growth factors, which control self-renewal, proliferation, apoptosis, differentiation, homing, quiescence, and others⁴⁹. On selective removal of osteoblasts causes a reduction in the number of HSCs where osteoblast increase is associated with an increase in HSC pool size in bone marrow. The effects of osteoblasts are due to direct cell interactions with HSCs through Jagged 1 (Jag-1) osteoblast and Notch receptor signaling on HSC which leads to an increase in HSC pool and signaling through the stromal Angiopoietin 1 (Ang-1) and Tie-2 receptor on HSC causing preserved HSC quiescence in the niche⁵⁰.

The next stage in HSC or osteoclast precursor cells as a response of mechanical force is the mobilization of osteoclast precursors including the release of cells into the circulation of bone marrow and homing from the bloodstream to the tissues. This mobilization of osteoclast precursors requires a variety of molecules and includes cytokines like granulocyte-macrophage colony stimulating factor (GM-CSF), IL-1β, IL-7, IL-3, IL-12, stem cell factor (SCF) and flt-3 ligand (Flt-3L), chemokines include IL-8, macrophage inflammatory protein-1α (MIP-1α) and stromal cell-derived factor-1 (SDF-1)⁵¹. SDF-1 is the most important chemoattractant for SC, which is an SC survival factor and is also as an SC attachment regulator with ECM or with stromal cells. When SDF-1 binds to its receptor CXCR4 makes a strong retention signal for HSC and progenitor cells fixed in the niche⁵². Decreasing concentration of SDF-1 and CXCR4 expression by some factors including mechanical forces can cause cell release into the blood circulation towards the target tissue. In addition, there are three chemokines to draw osteoclast progenitor cells to the desired tissue of CK β-8, regulated upon activation of T-expressed and secreted (RANTES) and MIP-1α cells. These three chemokines are produced by osteoblasts, osteoclasts and T cells and bind to CCR1 and CCR5 receptors in osteoclast progenitor cells. Once in the tissue, the osteoclast progenitor cells will continue the process of differentiation into mature cells by the help of other cytokines⁵³.

The involvement of osteoblastic lineage cells is needed in affecting the fate of HSC. Osteoblastic lineage cells prove osteopontin (OPN) act as a negative regulator of HSC pool size inhibiting HSC proliferation, trigger HSC apoptosis and affecting Jag-1 and Ang-1 expression by stromal cells. Stromal-derived factor-1 (SDF-1) produced by mesenchymal cells and osteoblasts is a major chemoattractant as some hematopoietic progenitors, including HSC⁵⁴.

On the other hand, osteoclast is also involved in mobilizing HSC in response to stress and pharmacological treatment. Activation of osteoclasts in HSC stress-induced mobilization through the production of proteolytic enzymes required for the stability of HSC niches. Osteoclast inhibition also increases HSC mobilization and reduces the primitive amount of HSC in bone marrow⁵⁵. Thus, the modulation of osteoclast activity will have an impact on HSC. In particular, in rats lacking osteoclast activity causes severe osteopetrosis associated with extramedullary hematopoiesis. This suggests that osteoclasts play a role not only in regulating or preserving but also in the early formation of HSC niches⁵⁶.

CONCLUSION:

It can be concluded that the mechanical force received by the mechanically induced alveolar bone remodeling process is responded directly by the MSC through several mechanisms to differentiate into osteoblasts, whereas HSCs cannot response directly to differentiate into osteoclasts but it is mediated by cells osteoblastic lineage including MSC.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 27.01.2022 Modified on 21.05.2022

Research J. Pharm. and Tech 2023; 16(1):123-128.

DOI: 10.52711/0974-360X.2023.00023