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TGF-β SIGNAL TRANSDUCTION IN ORO-FACIAL HEALTH AND NON-MALIGNANT DISEASE (PART I)

Department of Oral and Dental Science, Division of Oral Medicine, Pathology and Microbiology, Bristol Dental Hospital and School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK;

Correspondence: ^* corresponding author, Stephen.prime{at}bristol.ac.uk

Abstract

(I) Introduction

(II) TGF-β Ligand

(III) Signaling Pathways

(A) TGF-β RECEPTORS

(B) SMAD PROTEINS

(C) SMAD STRUCTURE

(D) SMAD FUNCTION

(E) SMAD CO-FACTORS, CO-ACTIVATORS, AND CO-REPRESSORS

(F) REGULATION OF RECEPTOR/SMAD FUNCTION

(G) ALTERNATIVE SIGNALING PATHWAYS

(H) NEW MODULATORS OF THE TGF-β RESPONSE

(IV) TGF-β Function

(A) GROWTH INHIBITION

(B) APOPTOSIS

(C) EXTRACELLULAR MATRIX (ECM) ELABORATION

(D) ANGIOGENESIS

(E) IMMUNOSUPPRESSION

(V) Role of TGF-β in Craniofacial Development and Oral Disease

(A) SKELETAL DEVELOPMENT

(B) PALATOGENESIS

(C) TOOTH MORPHOGENESIS

(D) WOUND HEALING

(E) FIBROTIC DISORDERS

(F) PERIODONTAL DISEASE

(G) LICHEN PLANUS

(VI) Concluding Remarks

Acknowledgments

REFERENCES

	Abstract

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Key Words: TGF-β • oro-facial • health • disease

	(I) Introduction

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Transforming growth factor-β (TGF-β) is a ubiquitous peptide that is expressed by nearly all cell types and is known to regulate an extensive array of cellular processes, including proliferation, differentiation, extracellular matrix (ECM) elaboration, hematopoeisis, angiogenesis, immune responses, and cell death (Massagué et al., 2000; Siegel and Massagué, 2003). In the present review, we summarize what is currently known about the activation of the peptide, together with the biochemical pathways by which the protein elicits a cellular response. The fact that TGF-β is multi-functional has meant that the peptide is increasingly being recognized as being of fundamental importance in a variety of normal physiological processes and in the pathogenesis of certain disease processes. We review the involvement of TGF-β in normal and pathological processes of the oral-facial tissues and include the embryonic development of the palatal shelves and teeth, followed by a consideration of disorders of fibrosis and the immune system. In a second review (also in this issue of Crit Rev Oral Biol Med), the role of TGF-β in epithelial malignancy, particularly with reference to the pathogenesis of oral cancer, is discussed.

	(II) TGF-β Ligand

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TGF-β is a member of a large family of structurally related growth and differentiation factors that also includes the activins and the bone morphogenic proteins (BMP; Massagué, 1990). There are three TGF-β isoforms in humans—TGF-β1, TGF-β2, and TGF-β3—the amino acid sequences of which are 70–80% homologous and encoded by distinct genes located to 19q13.1-q13.3, 1q41, and 14q24, respectively (Fujii et al., 1986; Barton et al., 1988). The wide distribution of expression of each isoform during embryogenesis suggests that the absence of a single TGF-β gene would not be compatible with normal development. The development of TGF-β null mice, however, not only showed that such mice could survive, albeit with limited post-natal survival, but also the absence of specific TGF-β isoforms resulted in specific non-overlapping phenotypes. These findings, therefore, excluded theories of redundancy among the different TGF-β isoforms (Erickson, 1993). What is now known is that the TGF-β isoforms exhibit overlapping, but distinct, temporal and spatial patterns of expression in vivo. In broad terms, TGF-β1 is expressed in epithelial, hematopoietic, and connective tissue cells, TGF-β2 in epithelial and neuronal cells, and TGF-β3 primarily in mesenchymal cells (Massagué, 1998). In a comprehensive review, Kulkarni et al.(2002) summarized the broad spectrum of findings that have resulted from TGF-β transgenic and gene knockout studies. TGF-β1^–/– null mice display strain-dependent death at mid-gestation, due to defective yolk sac vasculogenesis, progressive T-cell-dependent inflammation and autoimmunity, increased nitric oxide production, decreased bone mass and elasticity, defects of IgG, IgM, and IgE, and colon cancer. TGF-β2^–/– null mice exhibit multiple developmental defects, including cardiac, lung, craniofacial, limb, spinal column, eye, inner ear, and urogenital defects, all of which contribute to perinatal lethality. TGF-β3^–/– null mice die within 24 hours of birth, due to a failure of palate shelf fusion and delayed lung maturation.

TGF-β is secreted as either a small or large latent complex. The small latent complex consists of the carboxy terminal of the TGF-β dimer linked covalently to the amino terminus of the TGF-β precursor (latency-associated peptide; LAP). The large latent complex is composed of the small latent complex linked by disulphide bonds to the latent TGF-β-binding protein (LTBP), an ECM protein that belongs to the fibrillin family of proteins and which has a central role in the processing and secretion of TGF-βs. Several other ECM proteins have also been reported to bind TGF-β1 in vitro, including fibronectin, collagen IV, fibromodulin, decorin, and biglycan. These molecules target latent TGF-β to the ECM and are thought to ‘serve’ activated TGF-β to the signaling TβR-I and TβR-II receptors. The restricted pattern of expression of these binding molecules, therefore, is not only critical for the bio-availability of the peptide, but also is known to modulate individual TGF-β isoform activity (Saharinen et al., 1999).

The small latent complex is released from LTBPs by proteolysis, and then the ligand is activated by disruption of the covalent bonds that bind it to LAP (Khalil, 1999; Annes et al., 2003). This can be achieved by:

1. physio-chemical processes—acidic cellular micro-environment, extremes of pH, -radiation, reactive oxygen species;
   
2. enzymatic and protein interactions—proteases (plasmin, cathepsin G, calpain, MMP 2 and MMP 9), cell-cell interactions, glycosidases, thrombospondin, integrins vβ6 and vβ8; and
   
3. drugs/hormones—anti-estrogens, retinoids, vitamin D3 and derivatives, glucocorticoids.
   

The vβ6 integrin activates TGF-β1 and TGF-β3 by inducing a conformational change in the small latent TGF-β complex (Munger et al., 1999; Annes et al., 2003). Similarly, vβ8 also activates small latent TGF-β complexes and inhibits epithelial cell growth in a TGF-β-dependent way (Cambier et al., 2000; Mu et al., 2002). In 1989, Sato and Rifkin showed that latent TGF-β could be activated by co-culture of pericytes and smooth-muscle cells (Sato and Rifkin, 1989). It is now known that the latent TGF-β complex is bound to the cell surface of the smooth-muscle cells by a mannose-6-phosphate/insulin-like growth factor receptor (M6P/IGFII-R), and, after forming a complex with the urokinase plasminogen activator (uPA) receptor, plasmin is released from its precursor molecule plasminogen to facilitate activation of TGF-β (Godar et al., 1999).

	(III) Signaling Pathways

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(A) TGF-β RECEPTORS
TGF-β initiates signaling by the assembly of receptor complexes (Shi and Massagué, 2003; de Caestecker, 2004). Three major classes of receptor proteins (TβR-I, TβR-II, and TβR-III) have been identified by affinity cross-linking and by cDNA cloning. The genes encoding the receptors are located to chromosomes 9q33-34, 3p22, and 1p32-33 (TβR-I, TβR-II, and TβR-II, respectively; Mathew et al., 1994; Johnson et al., 1995).

TβR-I and TβR-II are protein kinases that contain an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic serine-threonine kinase domain. The type I receptor is distinguished by a highly conserved GS domain containing a repetitive glycine-serine motif between the transmembrane and kinase domains (Rosenzweig et al., 1995). Following binding of the TGF-β molecule to TβR-II, TβR-I is recruited to form a heterotetrameric complex. The constitutively active TβR-II then phosphorylates TβR-I on serine residues within its GS domain (Fig. 1; de Caestecker, 2004). TβR-III (β-glycan), the most abundant of the receptor types, is not directly involved in signaling but is thought to regulate TGF-β access to the signaling receptors TβR-I and TβR-II (Massagué, 1998).

View larger version (61K): [in this window] [in a new window]   Figure 1. TGF-β receptor activation. TGF-β initiates signaling by the assembly of receptor complexes involving two transmembrane serine-threonine kinase receptors (TβR-I and TβR-II). Following binding of TGF-β to TβR-II, TβR-I is recruited to form a heterotetrameric complex and is phosphorylated at serine residues within its GS domain by the constitutively active TβR-II. The activated TβR-I then activates a cascade of downstream signaling events that ultimately regulates gene transcription.

(C) SMAD STRUCTURE
Based on structural and functional considerations, Smads fall into 3 subfamilies, namely, the receptor-activated Smads (R-Smads; Smad1, Smad2, Smad3, Smad5, and Smad8), the common-mediator Smad (Co-Smad; Smad4), and the inhibitory Smads (I-Smads; Smad6 and Smad7; Fig. 2). Whereas Smad4 has a critical role in signaling by all the TGF-β superfamily members, R-Smads and I-Smads demonstrate pathway specificity and are selectively activated by different receptors. Smad2, Smad3, and Smad7 are activated primarily in response to TGF-β1 (Fig. 3), whereas Smad1, Smad5, and Smad8 are substrates of the BMP type I receptor and mediate BMP signaling. At their N- and C-termini, R-Smads and Co-Smads have highly similar amino-acid sequences termed ‘Mad homology domains’, MH1 and MH2, respectively (Attisano and Wrana, 2000). The MH1 domain predominantly mediates DNA binding and assists in nuclear translocation, whereas the MH2 domain is responsible for receptor interaction, Smad oligomerization, and transcriptional activation (Pierreux et al., 2000; Xiao et al., 2000). The MH1 and MH2 domains are separated by a variable proline-rich linker region which contains multiple consensus phosphorylation sites for mitogen-activated protein kinases (MAPKs) and, in the case of Smad4, a segment adjacent to the MH2 domain known as the Smad4 activation domain (SAD). SAD is essential for the mediation of signaling processes through its ability to confer transcriptional activity by binding to nuclear co-factors (de Caestecker et al., 2000). Although the C-terminal domain of the I-Smads is similar in structure to that of the R-Smads, the N-terminal domain fails to show significant homology (Souchelnytskyi et al., 1998).

View larger version (30K): [in this window] [in a new window]   Figure 2. Structure of Smad proteins. The R and Co-Smads show considerable homology within both the MH1 and MH2 domains. The MH domains are separated by a variable proline-rich linker region, which, in the case of Smad4, contains a Smad activation domain (SAD). **Smad2 is unable to bind directly to DNA, due to a 30-amino-acid insertion within exon3 of the MH1 domain. I-Smads have C-terminal domains structurally similar to R and Co-Smads. The N-terminus, however, fails to show significant homology.

View larger version (49K): [in this window] [in a new window]   Figure 3. Smad signaling. The activated TβR-I kinase phosphorylates the R-Smads, Smad2 and Smad3, which then form heterodimers with the Co-Smad, Smad4. The complex translates to the nucleus and regulates gene transcription by binding directly to DNA via interactions with DNA-binding proteins and/or transcriptional co-activators and co-repressors. The transcription of the I-Smad, Smad7, is induced, and Smad7 exits the nucleus to control the intensity and duration of signaling via a negative feedback mechanism.

Upon TGF-β-induced receptor activation, Smad2 and Smad3 are transiently recruited to the receptors via chaperone molecules such as membrane-associated SARA (Tsukazaki et al., 1998). Phosphorylation by TβR-I unmasks the NLS of the R-Smads such that they are released back into the cytoplasm, where they form heterotrimeric complexes with Smad4. Although the exact mechanisms of nuclear import are not completely understood, it is postulated that Smad4 either co-translocates with the R-Smads by utilizing the latter’s nuclear import function (Pierreux et al., 2000) or transports separately using its own nuclear import mechanism (Fink et al., 2003; Xiao et al., 2003). Once inside the nucleus, R-Smads mask the NES of Smad4, and the complex is retained in the nucleus to facilitate transcriptional regulation (Watanabe et al., 2000).

Within the nucleus, Smads function as transcriptional regulators and modulate the expression of target genes. The MH1 domains of Smad3 and Smad4, but not Smad2, bind directly to a specific DNA sequence called the Smad-binding element (SBE; Shi et al., 1998). SBEs have been found in multiple TGF-β-responsive promoter regions in a variety of genes, including PAI-1 (Dennler et al., 1998), JunB (Jonk et al., 1998), and type VII collagen (Vindevoghel et al., 1998). Since Smad protein affinity for this cognate sequence (CAGAC) is very low, additional DNA contacts with two classes of proteins—DNA binding co-factors and transcriptional co-activators and co-repressors—are necessary for specific, high-affinity binding of a Smad complex to a target gene. To date, more than 40 transcription factors, co-activators, and co-repressors are known to interact with Smad proteins (Miyazawa et al., 2002).

It is becoming apparent that Smad2 and Smad3 regulate different subsets of target genes. Smad3/Smad4 complexes activate immediate early genes by binding to SBE core repeats of target promoters, whereas Smad2 mediates the transmodulation of immediate-early and intermediate genes and may antagonize the effects of Smad3; interestingly, Smad3 appears to regulate a different set of genes in keratinocytes and fibroblasts (Yang et al., 2003).

(E) SMAD CO-FACTORS, CO-ACTIVATORS, AND CO-REPRESSORS
Smad co-factors co-operate with activated Smads by binding only to those promoters that fulfill combined sequence specificity. For example, Smad2 and/or Smad3 can associate with c-Jun/c-Fos (AP-1; Zhang et al., 1998), ATF2 (Hanafusa et al., 1999), TFE3 (Hua et al., 1998), PEBP2/CBF, and the vitamin D receptor (Yanagisawa et al., 1999). These interactions may lead to either additive or antagonistic activities regarding gene transcription, depending on the structure of the target promoters.

The binding of the Smad complex to DNA leads to the recruitment of either transcriptional co-activators or co-repressors. p300 and CREB binding proteins (CBP) are transcriptional co-activators and function either by altering chromatin structure so that the underlying DNA sequences are exposed to the transcriptional apparatus (Workman and Kingston, 1998) or by directly recruiting RNA polymerase II to the promoter (Snowden and Perkins, 1998). Smad4 functions to stabilize the R-Smad-CBP/p300 interaction and, therefore, is considered to be an essential co-activator for Smad2/3-dependent transcriptional activation (Feng et al., 1998). In contrast, repression of Smad-activated transcription occurs through the action of co-repressors such as TGIF (Wotton et al., 1999) and the proto-oncogenes Ski and SnoN, which recruit histone deacetylases (Luo et al., 1999).

(F) REGULATION OF RECEPTOR/SMAD FUNCTION
There are several mechanisms by which the function of TGF-β receptors and Smads can be modulated. Receptor activation is modified through the actions of accessory receptors such as Betaglycan, Endoglin, and NMA, and through ligand-dependent endocytic trafficking of activated receptors (Tsang et al., 2000; Blobe et al., 2001a,b; Di Guglielmo et al., 2003). Further, a large variety of proteins has been identified that interact with both the receptor complexes and R-Smads to regulate function. The FYVE domain protein SARA, FKBP12, Hgs, Axin, ELF, Disabled-2, TRAP-1, FTLP, and SANE, together with organelles such as microtubules, can regulate function both positively and negatively (Lutz and Knaus, 2002; ten Dijke et al., 2002; de Caestecker, 2004; Wang and Donahoe, 2004).

In the nucleus, Smad binding to DNA is transient, and deactivation of Smad function occurs through the actions of I-Smads and through R-Smad degradation and post-translational modification. The I-Smad, Smad7, resides within the nucleus in the basal state, is induced in response to TGF-β, and functions via a negative feedback mechanism to control the intensity and duration of Smad signaling (Fig. 3). The direct association of Smad7 with receptor complexes prevents further recruitment and phosphorylation of R-Smads, while its ability to recruit Smurf-1 and Smurf-2 leads to receptor degradation (Ebisawa et al., 2001).

Once receptor signaling is abrogated, Smad2 and Smad3 are rapidly de-phosphorylated, presumably by an as-yet-unidentified R-Smad nuclear phosphatase (Reguly and Wrana, 2003). Evidence is accumulating to indicate that phosphorylated R-Smads are degraded via the ubiquitin proteosome system by the activity of E3 ubiquitin ligases, which function at both the cytoplasmic (Zhang et al., 2001) and nuclear levels (Lo and Massagué, 1999). In contrast, Smad4 is not normally subject to regulation by phosphorylation or ubiquitination, most probably because it functions as a common mediator and is required to be present in significant levels at all times. Analysis of recent data suggests that Smad4 is stabilized by a unique post-translational modification involving a small ubiquitin-like modifier-1 (SUMO-1) which prevents Smad4 ubiquitination-dependent degradation (Lee et al., 2003; Lin et al., 2003). Like the R-Smads, Smad7 also undergoes ligand-dependent ubiquitination and degradation, possibly through its association with the intracellular protein Arkadia (Koinuma et al., 2003).

(G) ALTERNATIVE SIGNALING PATHWAYS
Data are rapidly accumulating to implicate a variety of additional pathways, other than Smad complexes, in TGF-β signaling. These include several small GTPases (Edlund et al., 2002), PKC (Runyan et al., 2003), and phosphatidylinositol 3-kinase (PI3K; Higaki and Shimokado, 1999; Bakin et al., 2000). Of increasing interest is the ability of TGF-β to activate MAPKs, a large family of serine/threonine proteins that function to control gene expression. Three main groups of MAP kinases have been identified, including extracellular-regulated kinases (Erks), which are stimulated by growth factors and are associated with the regulation of cellular proliferation and differentiation, and c-Jun N-terminal kinases (JNK) and p38, both of which are activated by cellular stress and have been implicated in the process of cell death. All three MAP kinase groups are activated by TGF-β, with varying kinetics in different cell types (Hartsough and Mulder, 1995; Atfi et al., 1997; Frey and Mulder, 1997; Reimann et al., 1997; Hannigan et al., 1998; Hanafusa et al., 1999; Sano et al., 1999; Yu et al., 2002; Itoh et al., 2003). In some cases, activation is very rapid (from 10 to 30 min), suggesting that it might occur through a direct, Smad-independent, post-translational modification. In other cases, however, activation is slow (several hours), suggesting an indirect Smad-dependent transcriptional response (Engle et al., 1999; Kim et al., 2002; Yu et al., 2002; Dumont et al., 2003; Itoh et al., 2003). To add further complexity, MAP kinase pathways have been shown to modulate Smad signaling. Activation of Erks, for example, induces phosphorylation in the linker region of R-Smads, thereby inhibiting ligand-induced nuclear accumulation of R-Smads (Kretzschmar et al., 1999), and p38 induces ATF-2 phosphorylation, resulting in synergism with R-Smads and transcriptional activation (Sano et al., 1999).

The mechanisms linking the kinase pathways to TGF-β receptors are unclear although TGF-β-activated kinase 1 (TAK-1) has been shown to be phosphorylated following TGF-β stimulation and leads to the activation of JNK and p38 (Yamaguchi et al., 1995; Shirakabe et al., 1997; Takatsu et al., 2000). TAK-1 binding protein (TAB-1) has been identified as an activator of TAK-1 (Shibuya et al., 1996) and may link with TβR-I through HPK1 and XIAP (Yamaguchi et al., 1999; Zhou et al., 1999).

(H) NEW MODULATORS OF THE TGF-β RESPONSE
Recently, Cordenonsi et al.(2003) demonstrated that the reduction of endogenous p53 levels in HepG2 cells reduced the expression of TGF-β target genes and allowed cells that were normally growth-inhibited by the ligand to become refractory to the peptide. Furthermore, restoring p53 activity in a p53-null cancer cell line, which is normally insensitive to TGF-β signaling, resulted in Smad-dependent inhibition of cell growth. Analysis of the data demonstrates that p53 cooperates with Smads to mediate the TGF-β transcriptional response, but the implications of disrupting p53 activity, as occurs in many tumor cell types, are currently unknown.

The Runt family of transcription factors consists of 3 DNA-binding subunits (RUNX 1, RUNX 2, RUNX 3), each of which is capable of forming heterodimers with the TGF-β co-activator p300/CBP. All 3 RUNX members bind R-Smads, thymocytes from RUNX 2 transgenic mice are hypersensitive to TGF-β, and loss of RUNX 3, now recognized as a tumor suppressor (particularly in gastric carcinoma), not only induces cell proliferation but also blocks TGF-β-induced apoptosis (Ito and Miyazono, 2003).

	(IV) TGF-β Function

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TGF-β is a multi-functional cytokine that functions to inhibit growth and induce apoptosis in a variety of cell types, elaborate extracellular matrices, and suppress the immune response. These effects are summarized in Fig. 4 and are discussed in more detail below.

View larger version (43K): [in this window] [in a new window]   Figure 4. Cellular effects of TGF-β. TGF-β is a multi-functional cytokine that inhibits epithelial cell growth, induces apoptosis in a variety of cell types, stimulates new vessel growth, and is a potent immunosuppressant. In addition, TGF-β functions to elaborate the extracellular matrix.

Additional signaling molecules have been reported to be critical for the anti-proliferative response to TGF-β, but their importance has not yet been fully established (Petritsch et al., 2000; Aghdasi et al., 2001).

(B) APOPTOSIS
TGF-β can induce apoptosis (programmed cell death) in a variety of different cell types. Although suppression of the apoptotic inhibitor Bcl-xL and activation of certain caspases have been implicated, the mechanisms that trigger apoptosis following receptor activation are poorly understood. The septrin-like molecule ARTS, a novel mitochondrial protein, translocates into the nucleus coincident with the induction of apoptosis, and Daxx, a Fas-receptor-associated protein, has been shown to interact with TβR-II and subsequently activate the JNK/Map kinase pathway. Analysis of such data suggests that novel pathways, distinct from Smad signaling, are involved in TGF-β-induced apoptosis (Larisch et al., 2000; Perlman et al., 2001). However, Smad-dependent pathways are also involved in TGF-β-induced apoptosis, because the inhibitory protein, Smad7, can induce apoptosis in epithelial cells, possibly by inhibiting NFB (Lallemand et al., 2001) or by the activation of JNK, thereby demonstrating the potential for complex interplay between signaling pathways (Mazars et al., 2001). Further, TGF-β-activated Smads have been shown to induce the expression of Gadd45, and this, in turn, leads to p38-dependent apoptosis in murine hepatocytes (Yoo et al., 2003).

(C) EXTRACELLULAR MATRIX (ECM) ELABORATION
TGF-β has a marked effect on ECM composition. The peptide is chemotactic for fibroblasts and causes the synthesis and secretion of ECM molecules such as collagen I, collagen type IV, fibronectin, and tenascin. Further, TGF-β mediates the equilibrium between ECM-degrading proteases and their inhibitors, with the result that ECM proteins are elaborated (Sieweke and Bissell, 1994; Verrecchia and Mauviel, 2002).

(D) ANGIOGENESIS
It is generally accepted that TGF-β plays an important role in vascular remodelling, although its effects appear to be contextual and dependent on the presence of other regulators. Studies have shown that TGF-β can increase the production of vascular endothelial growth factor (VEGF), enhance the effects of basic fibroblast growth factor (bFGF), and inhibit endothelial cell migration. As such, TGF-β has been identified as an important regulator of new vessel growth, vascular network formation, and the establishment and maintenance of vessel wall integrity (Pepper, 1997).

(E) IMMUNOSUPPRESSION
TGF-β has significant anti-inflammatory functions. The peptide modulates the proliferation and differentiation of lymphocytes, macrophages, and dendritic cells and, therefore, regulates both antigen- and non-antigen-specific immune processes. The overall response is dependent on the differentiation status of the target cells and the presence of other cytokines; in general, however, TGF-β inhibits B- and T-cell proliferation, inhibits MHC class II expression, and stimulates apoptosis. The net effect is that TGF-β functions as a potent immunosuppressive molecule (Letterio and Roberts, 1998; Dong et al., 2001; Dennler et al., 2002).

	(V) Role of TGF-β in Craniofacial Development and Oral Disease

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The signaling pathways activated by members of the TGF-β superfamily are known to play critical roles in mammalian development. It is perhaps not unexpected, therefore, that defects in TGF-β signal transduction have been shown to be responsible for several developmental disorders, and that de-regulated TGF-β activity has been implicated in the pathogenesis of a variety of human diseases (Blobe et al., 2000; Massagué et al., 2000). In this article, we will focus specifically on the role of the TGF-β isoforms in craniofacial development and in non-malignant oral disease.

(A) SKELETAL DEVELOPMENT
The abundant and overlapping expression of each TGF-β isoform in bone emphasizes the importance of these molecules in normal hard-tissue development and function. Defects of bone have been reported predominantly in TGF-β2^–/– null mice, leading to numerous defects of the craniofacial, axial, and appendicular skeleton (Sanford et al., 1997). Targeted over-expression of TGF-β2 to osteoblasts in transgenic mice causes an imbalance between osteoblastic and osteoclastic activity and leads to a phenotype that is characterized by bone loss such that it resembles either osteoporosis or hyperparathyroidism. Interestingly, there is also a delay in the ossification of bones and the mineralization of sutures, together with a clavicular malformation that resembles cleidocranial dysplasia (Erlebacher and Derynck, 1996; Kreiborg et al., 1999; Mundlos, 1999; Massagué et al., 2000).

(B) PALATOGENESIS
In mammalian development, the formation of the palate is required to separate the oropharynx from the nasopharynx. Palatogenesis is a multi-step process involving palatal shelf growth and elevation, followed by fusion of the paired shelves and the disappearance of the medial edge epithelium (MEE) from the midline to allow for mesenchymal confluence (Ferguson, 1988). Defects in any of these processes lead to cleft palate, one of the most common birth defects in humans (Chenevix-Trench et al., 1992). Studies with transgenic mice have implicated the involvement of more than 20 different genes in this process. With regard to the TGF-β isoforms, a cleft palate develops in 100% of TGF-β3^–/– null mice (Proetzel et al., 1995) but occurs in only 23% of TGF-β2-deficient animals (Sanford et al., 1997) and is not seen in TGF-β1 knockouts (Shull et al., 1992; Kulkarni et al., 1993). Further, the inhibition of TGF-β3 results in a failure of plate fusion in vitro (Brunet et al., 1995), and the addition of TGF-β3 to cultures of palatal shelves from TGF-β3-deficient mice is able to reverse the phenotype completely (Kaartinen et al., 1997; Taya et al., 1999). TGF-β3 also induces an epithelial-mesenchymal transdifferentiation of the MEE (Kaartinen et al., 1997; Sun et al., 1998), possibly by regulating the expression of MMPs (Blavier et al., 2001) and proteoglycans (Gato et al., 2002) by Smad2-dependent mechanisms (Cui et al., 2003). These findings have been confirmed recently by Dudas et al.(2004), who showed that TGF-β3-induced palatal fusion was mediated by the Alk-5/Smad pathway.

A role for TGF-β3 in the development of cleft palate in humans is less clear. While some workers have failed to find a link between TGF-β3 and oral clefts (Beaty et al., 2001), others have demonstrated polymorphisms in the TGF-β3 gene that have been linked with the disorder (Lidral et al., 1998); these allelic variants may interact with other risk factors, such as maternal tobacco use, in the development of this syndrome (Romitti et al., 1999).

(C) TOOTH MORPHOGENESIS
TGF-β isoforms are thought to play a fundamental role in the histomorphogenesis of developing teeth. Dental abnormalities have been described in TGF-β^–/– null mice (D’Souza and Litz, 1995; D’Souza et al., 1998), and inactivation of the TβR-II gene leads to accelerated tooth development (Chai et al., 1999). These findings have subsequently been extended, and it has been postulated that TGF-βs (TGF-β1 and -β3), derived from the enamel organ and immobilized and activated by components of the basement membrane, induce odontoblast differentiation. Odontoblasts, in turn, then express TGF-β, which acts in an autocrine manner to stimulate the secretion of predentin and dentin (Lesot et al., 2001). This proposal is consistent with observations showing the presence of TGF-β isoforms in dentin matrices (Cassidy et al., 1997) and both TGF-β isoforms and TβR-I and TβR-II in odontoblasts (Sloan et al., 1999, 2000). These findings suggest an active TGF-β signaling complex at the primary site of dental hard-tissue formation. Interestingly, members of the TGF-β super-family also seem to be important in hard-tissue formation after pulpal injury and have the potential to induce odontoblast differentiation (Ruch et al., 1995). Further, sequestered TGF-β appears to be released from dentin following tissue injury, leading to the generation of reactionary/reparative dentin in mature teeth (Magloire et al., 2001), a repair process that may have significant implications for the dental profession in future years. However, targeted over-expression of TGF-β1 specifically to tooth germs in transgenic mice results in a phenotype similar to dentin dysplasia, such that excess collagen deposition and defects can be found in tooth mineralization (Thyagarajan et al., 2001).

The role of BMPs and their receptors in tooth morphogenesis is less clear (Cheifetz, 1999). BMP-2, BMP-4, and BMP-7 expression appears to be temporally related, with different expression patterns in the epithelium and mesenchyme associated with the bud, cap, and bell stages of tooth morphogenesis; similarly, BMP receptor expression is also variable. Further work is clearly required in this area, not least because the situation is complicated by species variation, ligand and receptor redundancy, and an unknown contribution of ligand from maternal sources.

(D) WOUND HEALING
The role of TGF-β in the wound-healing process is controversial. Many animal models of impaired wound healing have shown that reduction of endogenous TGF-β1 in the wound bed underlies the defective repair process. This concept, however, has recently been questioned, because TGF-β1^–/– and Smad3^–/– null mice showed accelerated wound healing and a reduction in the area of granulation tissue (Ashcroft et al., 1999; Koch et al., 2000). The findings may be explained in terms of the function of different TGF-β isoforms (O’Kane and Ferguson, 1997). TGF-β1 and TGF-β2 increase significantly within 24 hours of an incisional wound, and later, TGF-β3 is elevated when TGF-β1 levels decrease, suggesting a reciprocal relationship between TGF-β1 and TGF-β3 during wound healing. Both TGF-β3 and a polyclonal neutralizing antibody to TGF-β1,2 significantly reduce scarring in rat incisional wounds (Shah et al., 1992, 1994), possibly because the ratio of TGF-β3 relative to TGF-β1/TGF-β2 has been altered early in the wound-healing cascade. Further, preventing the activation of TGF-β1 by competitive inhibition of binding of the LAP at the M6P/IGFII-R has a marked anti-scarring effect (McCallion and Ferguson, 1996).

The observation that there are decreased levels of TGF-β1 and TGF-β2 in situations of impaired wound healing has prompted the use of exogenous TGF-βs in the management of these problems (Cox et al., 1992; Beck et al., 1993; Robson et al., 1995). Of particular significance to the oral physician in this context is the development of oral mucositis following chemotherapy. Topical application of TGF-β3 prior to chemotherapy with 5-Fluorouracil in hamsters resulted in a significant reduction in oral mucositis (Sonis et al., 1997). Despite these early encouraging results, however, a double-blind, placebo-controlled, multi-center phase II clinical trial has shown that TGF-β3 is not effective in the prevention or alleviation of chemotherapy-induced oral mucositis (Foncuberta et al., 2001). In chronic wounds, high levels of proteases causing cytokine breakdown, the presence of underlying systemic disease, and the lack of vascularity at the wound site, together with the placebo effect of any clinical trial, could contribute to these clinical findings.

The situation is somewhat different in human skin exposed to solar ultraviolet irradiation (Quan et al., 2002). In these circumstances, there is increased expression of TGF-β1 and TGF-β3 but decreased expression of TGF-β2 (the predominant TGF-β isoform in normal skin epithelium); TβR-II is decreased and Smad7 is increased. Taken together, the changes are thought to drive ECM elaboration.

(E) FIBROTIC DISORDERS
Scleroderma (systemic sclerosis) is a disease characterized by vascular dysfunction and excessive production of ECM proteins, resulting in fibrosis of the subcutaneous tissues and viscera. Approximately 80% of patients have manifestations in the head and neck region, with dysphagia and reflux esophagitis being common. Other oro-facial problems include progressive trismus, stiffening of the tongue, and, occasionally, a widening of the periodontal membrane space without tooth mobility. The fact that TGF-β stimulates fibroblast proliferation and ECM elaboration suggests the importance of this cytokine in fibrotic disease. Indeed, it has been shown that fibroblasts from scleroderma patients show enhanced sensitivity to TGF-β (Cotton et al., 1998). The mechanisms underlying this hyper-responsiveness to TGF-β in scleroderma have recently been explained in terms of decreased expression of the inhibitory Smad, Smad7, in scleroderma fibroblasts compared with their normal counterparts (Dong et al., 2002).

Another fibrotic disease of relevance to the dental community is oral submucous fibrosis (OSF). This disorder is closely associated with the habit of chewing betel quid, it affects approximately 5 million people in the Indian subcontinent, and it is a potentially malignant condition (Pindborg et al., 1984). OSF is characterized histologically by the deposition of collagen in the oral submucosa, together with epithelial atrophy and dysplasia. The role of TGF-β in OSF is unknown, but it has been reported that the type I plasminogen activator inhibitor (PAI-1), a known Smad-responsive gene, is up-regulated in OSF (Dong et al., 2002), thus giving indirect evidence for enhanced TGF-β activity in OSF. Furthermore, it has been suggested that polymorphisms in the TGF-β gene may affect an individual’s susceptibility to this most debilitating of disorders (Chiu et al., 2002).

(F) PERIODONTAL DISEASE
TGF-β is one of several cytokines known to regulate inflammation and immune responses, and the fact that TGF-β mediates leukocyte recruitment, adhesion, and activation suggests that it has a key role to play in the host’s response to bacterial and immunological challenge. It is somewhat surprising, therefore, that there is not clearer evidence for its involvement in the pathogenesis of periodontal disease (Skaleric et al., 1997; Holla et al., 2002; de Souza et al., 2003; Ejeil et al., 2003). This may be due to several factors, including the multi-factorial nature of the disease, the complex interaction between and among different cytokines at the site of inflammation, and the technical difficulties associated with the measurement of active as opposed to total TGF-β.

(G) LICHEN PLANUS
Oral lichen planus is a chronic inflammatory disease that is characterized histologically by a dense sub-epithelial T-cell infiltrate and degeneration of basal keratinocytes; auto-reactive cytotoxic T-cells are known to trigger keratinocyte apoptosis (Sugerman et al., 2000). Recently, the role of TGF-β in the pathogenesis of oral lichen planus was reviewed by Sugerman et al.(2002). These authors suggested that, in view of the fact that TGF-β had potent immunosuppressive activity, possibly mediated by CD4+ TGF-β secreting Th3 regulatory T-cells which suppressed immune responses to self-antigens (Bridoux et al., 1997; Mason and Powrie, 1998), and that TGF-β could interfere with antigen presentation (Letterio and Roberts, 1998), a breakdown of TGF-β activation and/or signal transduction might occur at sites of inflammation in this disease process. This proposal is consistent with the identification of TGF-β+ T-cells in the sub-epithelial lymphocytic infiltrate, but not within the epithelium itself, of oral lichen planus tissues (Khan et al., 2003). Further, over-expression of Smad7 appears to be a characteristic feature of basal keratinocytes in active lichen planus lesions, suggesting that the TGF-β pathway is suppressed (Dr. A. Karatsaidis, personal communication).

Widespread autoimmune-like inflammatory disease is a characteristic of TGF-β1^–/– null mice (Dang et al., 1995; Kulkarni et al., 2002), and in animals where Smad3 function has been disrupted (Yang et al., 1999); replacement of TGF-β in animal models of autoimmune disease significantly ameliorates the disease process (Kuruvilla et al., 1991; Racke et al., 1991; Chen et al., 1998). Importantly, interferon gamma (IFN-) is known to inhibit the immunosuppressive activity of TGF-β1 by blocking TGF-β-induced phosphorylation of Smad3 (Ulloa et al., 1999), and it has been suggested that the balance between TGF-β1 and IFN- signaling determines the level of immunological activity in mucosal inflammatory disorders (Strober et al., 1997). It is conceivable, therefore, that in active lichen planus, over-production of IFN- by Thy1 CD4+ T-cells and/or over-expression of Smad7 down-regulates the immunosuppressive activity of TGF-β1 and induces MHC class II expression and CD8+ cytotoxic T-cell activity. In contrast, in quiescent lesions, the balance between IFN-gamma and TGF-β1 activity would change such that the immunosuppressive function of TGF-β1 would predominate.

	(VI) Concluding Remarks

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The past 10–15 years have seen significant advances in our understanding of the biochemical pathways associated with TGF-β signal transduction. These discoveries have laid the foundation for an exciting period of further exploration that is likely to be directed toward designing new therapeutic modalities to address some of the disease processes in which TGF-β has been implicated.

A tentative start has been made. Scientists are already examining the prospect of using BMPs to treat anomalies of bone such as fractures, osteoporosis, and periodontal defects and to facilitate osseous-integration of implants (King, 2001; Sykaras and Opperman, 2003). Further, the capacity of TGF-β to suppress immune responses raises the possibility that TGF-β substitutes and/or agonists may be used for the treatment of chronic autoimmune diseases, an approach with some experimental support (Prud’homme and Piccirillo, 2000; Prud’homme et al., 2001). In contrast, an antagonist of TGF-β is also likely to have significant value, primarily in the treatment of fibrotic disorders of the kidney, liver, and lung (Blobe et al., 2000), and also in the prevention of scar formation in the skin and oral mucosa (see above). A variety of different strategies has been used to develop TGF-β antagonists, including recombinant soluble betaglycan (Bandyopadhyay et al., 2002), a soluble type II TGF-β:Fc fusion protein (Muraoka et al., 2002; Yang et al., 2002), the histone deacetylase inhibitor trichostatin A (Rombouts et al., 2002), and retroviral gene therapy with dominant-negative TβR-II constructs (Huang and Lee, 2003). The use of peptides in a therapeutic capacity, however, is limited because of poor bioavailability, poor membrane penetration, and unfavorable pharmacokinetics. One of the challenges for the future, therefore, will be to develop new small molecules that can either mimic or antagonize the effects of TGF-β to produce a therapeutic gain in different disease processes. Further, the key will be to deliver these molecules in an organ-specific way to avoid deleterious side-effects.

The present review goes some way toward describing the importance of TGF-β in oral health and non-malignant disease; a second review (also in this issue of Crit Rev Oral Biol Med) examines the part that the peptide plays in oral malignancy. New information on activation and signaling pathways will provide new targets for therapeutic intervention, and the development of both TGF-β agonists and antagonists will expand the opportunities for intervention in common pathological processes. It is perhaps not an overstatement to say that exciting times are ahead for those who wish to be part of this rapidly expanding field.

	Acknowledgments

 
The authors are most grateful to the Shirley Glasstone Hughes Memorial Fund (British Dental Association) for the support of MP. We thank J. Beddoe and L. Jones for help in preparation of the manuscript.

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Critical Reviews in Oral Biology & Medicine, Vol. 15, No. 6, 324-336 (2004)
DOI: 10.1177/154411130401500602


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