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1Department of Dental Medicine, Stony Brook University, School of Dental Medicine, Stony .... dent., Professor and Associate Dean for Clinical Affairs, Stony.
MINI-REVIEW

Journal of

PERIOSTIN: Role in Formation and Maintenance of Dental Tissues

Cellular Physiology

GEORGIOS E. ROMANOS,1* KETKEE P. ASNANI,2 DINESH HINGORANI,2 2 AND VIJAY L. DESHMUKH 1

Department of Dental Medicine, Stony Brook University, School of Dental Medicine, Stony Brook, New York

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Department of Periodontology, Dr. D.Y. Patil Vidyapeeth, Dental College and Hospital, Pune, Maharashtra, India

The matricellular protein periostin is strongly expressed in collagen-rich connective tissues such as periodontal ligaments (PDLs), skeletal muscle, adipose tissue, tendons, skin, and bone. It is prominent in tumorigenesis, angiogenesis, and cardiac repair. It is localized in the periosteum and PDL, where it is seen in the cytoplasmic extensions of the PDL fibroblasts. It plays a key role in morphogenesis, postnatal development, and maintenance of the tooth, and related structures. It mediates and augments collagen fibrillogenesis, cell migration, adhesion, response to mechanical stress, and wound healing. It has been shown to be an integral regulator of periodontal disease pathogenesis and repair. This review focuses on the various functional aspects of periostin in dental connective tissue development and maintenance. J. Cell. Physiol. 229: 1–5, 2014. ß 2013 Wiley Periodicals, Inc.

The extracellular matrix (ECM) in tissue provides structural support to the cells, in addition to performing various other important functions. It is the defining feature of connective tissue. Integrity of the ECM is essential for maintaining the normal structure and function of connective tissues. After being secreted locally by cells, the ECM gets organized into a complex meshwork that provides physical support to cells, tissues, and organs. Initially thought to act only as a scaffold, the ECM is now known to provide a series of signals to cells, regulating all aspects of their phenotype from morphology to differentiation (Mariotti, 1993). It provides molecular signals to the resident fibroblast populations that are essential for maintenance and turnover of the ECM. Thus, it regulates cell behavior (Wen et al., 2010). The ECM proteins are known to play a crucial role in tissue development, wound repair, and initiation and progression of pathologic alterations (Mariotti, 1993). Bornstein and Sage (2002) gave the term “matricellular” to a group of extracellular proteins that do not contribute directly to the formation of structural elements but serve to catalyze cell–matrix interactions and cell function. These proteins characteristically contain binding sites for ECM structural proteins and cell surface receptors and may initiate or inhibit and modulate activities of specific growth factors (Roberts, 2011). The matricellular proteins have certain typical characteristics that make them distinctive. They characteristically bind to many cell-surface receptors, growth factors, cytokines, proteases, and components of the ECM and express high levels during development or injury. Mice with target disruption (knockout) of some matricellular protein genes express abnormal phenotypes. This hints at the functional importance of matricellular proteins in inducing other matrix proteins. The matricellular proteins are affected by their local environment, which guides their function in the tissues (Bornstein, 2009). Examples of matricellular proteins include the CCN family of proteins; osteopontin; periostin; SPARC family members; tenascin-C; thrombospondins1 and 2; WISP1, 2, and 3; Nov; Galectin 1, 2, 3, 4, 8, and 9; Cyr61; and bone sialoprotein (Hamilton, 2008). Periostin was first identified by Takeshita et al. (1993). Norris et al. (2008) were the first ones to propose that periostin be classified as a matricellular protein. ß 2 0 1 3 W I L E Y P E R I O D I C A L S , I N C .

Periostin—A Matricellular Protein

Periostin gene (POSTN) expression was first identified using subtractive hybridization techniques on the mouse osteoblastic cell line MC3T3-E1 and initially named osteoblast-specific factor 2 (OSF-2) (Takeshita et al., 1993). Because several other factors at that time were called OSF-2, the protein was renamed periostin, based on its localization in the periosteum and periodontal ligament (PDL) (Horiuchi et al., 1999). In humans, the periostin gene is located on chromosome 13, at map position 13q13.3, and the protein is 835 amino acid in size (Hamilton, 2008). The 90-kDa ECM protein is composed of an amino-terminal in the EMILIN family (EMI domain), a tandem repeat of four fas I domains (RD 1–4), a carboxyl-terminal region (CTR), and a heparin binding site at its C-terminal end (Kudo, 2011). Therefore, based on these typical fas I domains, it is characterized as a member of the fasciclin-I family. The family of fasciclin genes consists of four highly allied members: periostin, bIG-H3 (transforming growth factor-b-inducible protein), stabilin-1, and stabilin-2 (Norris et al., 2007). Periostin and bIG-H3 are most similar, as structurally they both share uninterrupted tandem repeats of four fas 1 domains. Periostin directly interacts with type I collagen, fibronectin, and Notch1 through its EMI domain, through its fas I domains with

Conflict of interest: The authors declare no conflicts of interest with respect to the research, authorship, and/or publication of this article * Correspondence to: Georgios E. Romanos, DDS, PhD, Prof. med. dent., Professor and Associate Dean for Clinical Affairs, Stony Brook University, School of Dental Medicine, 184C Sullivan Hall, Stony Brook, NY 11794-8700. E-mail: [email protected] Manuscript Received 28 January 2013 Manuscript Accepted 17 May 2013 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 23 May 2013. DOI: 10.1002/jcp.24407

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ROMANOS ET AL. tenascin-C and BMP-1, and with laminin g2, aiding in wound healing, through interactions yet unknown (Takayama and Kudo, 2012). Periostin is highly expressed in collagen-rich connective tissues, which are subjected to constant mechanical stresses, aiding in effective transmission and distribution. It has been associated with various tissues and pathologies including bone, PDLs, skin, cardiac valves, muscle injury, vascular injury, myocardial infarction, epithelial ovarian cancer, colorectal cancer, pulmonary vascular remodeling, bronchial asthma, and oral cancer. It is also known to be involved in the pathogenesis of obesity and type 2 diabetes (Bolton et al., 2006). Periostin in Non-Dental Pathologies Tumorigenesis

Periostinis found to be overexpressed in several human cancers such as lung, colon, head and neck, breast, ovarian, and pancreatic (Ruan et al., 2009). It has been suggested that periostin plays a role in tumor development and metastasis (Siriwardena et al., 2006; Ruan et al., 2009). The fas 1–2 domain of periostin is involved in cell adhesion, thereby facilitating tumor growth and angiogenesis (Orecchia et al., 2011). It significantly enhances angiogenesis by up-regulating FlK-1/KDR (vasculoendothelial growth factor receptor-2) by endothelial cells through the avb3 focal adhesion kinase (FAK) mediated signaling pathway, thus offering a growth advantage to tumors (Ku¨hn et al., 2007). Tumors expressing periostin show a higher density of blood vessels, and periostin has been found to promote capillary formation in a concentration-dependent manner (Siriwardena et al., 2006). Epithelial–mesenchymal transition (EMT), an important step in tumor invasion, is also facilitated by periostin (Ruan et al., 2009). Periostin promotes lymphangiogenesis in head and neck cancer through Src and Akt activity and by augmenting VEGF-C (vasculoendothelial growth factor 2-C) (Kudo et al., 2012). Periostin plays an important role in anchoragedependent growth and invasion of head and neck squamous cell carcinoma (Kudo et al., 2006). Cardiac repair

Periostin plays an important role in the development of the embryonic heart by increasing collagen fibrillogenesis and compaction. It also plays a role in differentiating mesenchymal cells to a fibroblast lineage. It is expressed in the epicardium, valve leaflets, and supporting structures (Niu et al., 2008; Snider et al., 2008). Cardiomyocytes are the regenerative cells in a heart injury, but mammalian hearts respond by scar formation and not cardiomyocyte proliferation. Ku¨hn et al. (2007) in their study showed that periostin bound to a degradable gelfoam matrix improved mammalian cardiac function after myocardial infarction by initiating the cardiomyocyte cell-cycle activity. Periostin affects the cycling of differentiated cardiomyocytes in a concentration-dependent mechanism through integrins. When compared with controls, periostin-treated hearts showed a reduction in infarct size and improved ventricular remodeling, thus decreasing fibrosis. They also showed increased arteriolar density as compared to controls. Thus by stimulating proliferation of endogenous cardiomyocytes, periostin may provide an innovative approach to mitigate heart failure and induce myocardial repair. Diabetes and obesity

Bolton et al. (2006) for the first time associated periostin with obesity and type 2 diabetes in Psammomys obesus (sand rat). They hypothesized that it may play a homeostatic role in the JOURNAL OF CELLULAR PHYSIOLOGY

response of skeletal muscle to type 2 diabetes. Periostin was highly expressed in the adipose tissue in both visceral and subcutaneous depots, suggesting its role in repair or expansion of adipose tissue. Periostin is also a biomarker for disease progression in chronic kidney disease and pulmonary fibrosis (Guerrot et al., 2012). Bronchial asthma

Asthma is a chronic inflammatory disease of the airway. Woodruff et al. (2009) described T-helper type 2 (Th2) as the major subphenotype causing inflammation in asthma. These Th2 cells produce IL-13, which in turn induces the expression of periostin by the epithelial cells of the bronchi. This process is thought to mediate airway hyper-responsiveness, inflammation, mucous metaplasia, and activation and proliferation of airway fibroblasts in asthma. All this leads to adverse airway remodeling. Thus IL-13 is a therapeutic target for the treatment of asthma. A trial with the drug lebrikizumab, whose effect was superior in patients with higher levels of circulating periostin, further validates this premise (Kraft, 2011). Role of Periostin in Dental Tissues Embryonic and postnatal dental tissues

Rios et al. (2005) demonstrated that periostin is expressed in the developing teeth at sites of epithelial–mesenchymal interaction. This suggests that periostin plays a key role during tooth development and could be linked with deposition and organization of other ECM adhesion molecules. It may mediate various cellular events involved in maintenance of the integrity of adult teeth, particularly at the sites of hard–soft tissue interface (Suzuki et al., 2004). Findings in developing mouse mandibles have suggested that periostin serves as adhesive equipment at the sites of cell-tomatrix interaction. It induces the development of morphogenesis and aids in bearing mechanical forces that include occlusal forces and tooth eruption. In tooth germs at the cap stage and bell stage, periostin immunoreactivity was recognizable in the interface between the inner enamel epithelium and pre-odontoblasts, as well as in the mesenchymal tissues around the cervical loop and dental follicles. Periostin immunoreactivity was also found on the alveolar bone surface. In the incisors of both 7- and 21-day-old mice, an immunoreaction to periostin was uniformly localized in the lingual PDL. The immunoreaction to periostin was observed in the fibrous bundles in the PDL, indicating its role in the morphogenesis of the PDL and subsequent development. Immuno-localization of periostin was restricted to the cell membrane of the cytoplasmic extensions of the periodontal fibroblasts, and none was seen in the cytoplasm or the ground substance of mature PDLs (Suzuki et al., 2004). This highlights the function of periostin in the remodeling and metabolism of ECMs during tooth development. Immunohistochemical studies have revealed high levels of periostin expression in the PDL matrix (Horiuchi et al., 1999). The first detailed study to assess the importance of periostin in postnatal mouse development and its role in a wide spectrum of tissues and pathologic processes was carried out by Rios et al. (2005) by generating periostin-null (/) mice with a lacZ reporter gene. The periostin-null mice were dwarfed, with shorter and narrower skulls and undersized ribs and forelimbs that histologically showed reduced cartilaginous growth plates and cancellous bony trabeculae. Incisors showed widened PDLs and signs of abnormal remodeling and destruction of alveolar bone. Histologically, an increase in osteoclast activity was seen, along with inflammatory infiltrate composed mainly

PERIOSTIN AND DENTAL TISSUES

of neutrophils and fewer lymphocytes and plasma cells, hinting at an increased susceptibility to bacterial invasion. The structurally unstable PDLs indicated a rapidly progressive periodontitis-like disorder with a loss of the PDLs’ mechanical properties. The incisors revealed severe enamel and dentin matrix defects, although there was no change in ameloblast differentiation. Defects in ameloblast morphology and function resulted in secretion of inappropriate amorphous matrix and abnormal enamel structure, ultimately resulting in enhanced tooth wear (Rios et al., 2005). Thus, it was shown that periostin is critically important in maintaining the integrity of PDLs and is essential for postnatal development. Similar findings of Kii et al. (2006) also suggested that periostin is essential for the remodeling of collagen matrix in the shear zone in mice and that periostin-null mice showed eruption disturbances of incisors. Deletion of periostin leads to changes in expression profiles of many non-collagenous proteins, such as dentin sialophosphoprotein, dentin matrix acidic phosphoprotein-1, bone sialoprotein, and osteopontin in the incisor dentin (Dedbong et al., 2011). Hence, by effective remodeling of collagen matrix and induction of various non-collagenous proteins, periostin controls the morphogenesis of the tooth and periodontium. Collagen fibrillogenesis and tissue integrity

Collagen is a predominant component of ECM in the periodontium. The PDL is primarily composed of types I, III (Butler et al., 1975; Huang et al., 1991; Romanos et al., 1992), V, VI (Romanos et al., 1991), and XII (Karimbux and Nishimura, 1995) collagen. Collagen is responsible for the mechanical properties of the connective tissue and provides tensile strength. Collagen fibrillogenesis is a complicated process in which many ECM proteins are involved. Various studies have reported the co-localization and molecular interaction of periostin and collagen in the PDL (Suzuki et al., 2004; Kii et al., 2006; Norris et al., 2007). The molecular mechanism of periostin action in collagen cross-linking has been investigated, and the results showed that periostin interacts with BMP-1 and enhances the proteolytic activation of lysyl oxidase (LOX), an enzyme responsible for cross-link formation (Maruhashi et al., 2010). Together with tenascin-c, periostin acts as a scaffold that increases the deposition of BMP-1 into the fibronectin matrix to activate pro-LOX. The periostin stabilizes the precursor LOX, which then gets proteolyzed to LOX (Kudo, 2011). Thus, periostin aids in the formation of high stiffness collagen through effective collagen cross-linking. A correlation has been suggested between collagen fibril diameters and the mechanical properties of collagen-based connective tissues (Christiansen et al., 2000). By reducing the collagen diameter, the structural and functional integrity of collagen and, ultimately, the connective tissue is compromised. Norris et al. (2007) demonstrated reduced diameters of collagen fibrils in periostin knockout mice compared to wild-type mice, thereby resulting in defects in collagen fibril maturation and assembly. They even showed a reduction in collagen cross-linking. All this resulted in alterations of the biomechanical properties of connective tissues. Periostin is also known to play a role in osteoblast adhesion, differentiation, and survival. It was reported to support avb3 and avb5 integrin-dependent cell adhesion and cell motility of MC3T3-E1 and primary rat osteoblasts (Horiuchi et al., 1999). Periostin and avb3 are concomitantly expressed in human bone tissue, suggesting their role in osteoblast recruitment and attachment. Periostin regulates cell migration and survival through the FAK signaling pathway. Mechanical loading always has a positive effect on bone growth and development. Cells from the bone and PDL respond to stimulation by activation of JOURNAL OF CELLULAR PHYSIOLOGY

mechano-sensory signaling systems, cytoskeletal changes and ECM architecture reorganization to withstand these loads without damage (Ho et al., 2007). Where periostin þ/þ mice show improved bone mineral density, trabecular and cortical microarchitecture, and biomechanical properties in response to axial compression, periostin / mice are less affected. An up-regulation in the levels of periostin is seen with a concomitant down-regulation in sclerostin, an antagonist of bone formation. Elevated expression of periostin mRNA is associated with inhibition of sclerostin mRNA in bone after axial compression (Bonnet et al., 2009). Thus, under mechanical stress, periostin maintains bone integrity by stimulating osteoblast activity and suppressing the action of sclerostin by osteocytes, all through integrin signaling. Even the preferential expression of periostin in the periosteum, a major contributor to bone strength, suggests that it may be involved in bone microarchitecture and bone strength (Merle and Garnero, 2012). In teeth, the PDL is involved in transmission of forces resulting from mastication. Mechanical strain activates latent TGF-b1 (transforming growth factor- b1), a known prerequisite for up-regulation of certain pro-adhesive and matrixremodeling genes in fibroblasts. TGF-b1 is also required for matrix contraction. It in turn increases periostin mRNA levels in murine PDL fibroblasts (Rios et al., 2008). TGF-b regulates periostin expression not only through activation of the TGF-b receptors, but also through the FAK-src signaling pathway, leading to translocation of twist-1 to the nucleus and subsequent periostin activation (Merle and Garnero, 2012). It has also been seen that removal of mechanical forces or strain inhibited expression of periostin and twist mRNA in the PDL (Afanador et al., 2005). Thus, periostin is essential for maintaining the integrity of PDL fiber system in response to mechanical stress (Choi et al., 2011). In an experimental tooth model, after the imposition of mechanical stress, periostin mRNA was up-regulated in PDL compression sites, compared to tension sites (Wilde et al., 2003). In a mechanically challenging environment, periostin-null mice showed tissue and cellular defects, leading to a dramatic loss of periodontal support that in turn caused premature tooth loss or pathologic migration. The cementoblasts also failed to attach to the root surface, thereby resulting in a compromised attachment apparatus. But in the absence of a mechanically challenging environment (occlusal hypofunction) no periodontal defects developed. Decreasing the mechanical stress corrected the widened PDL and recruited cementoblasts to attach to the root surface (Rios et al., 2008). Similarly, Choi et al. (2011) study of 45 Wistarrats, showed that in the absence of mechanical stress, the PDL fiber system undergoes degradation, and periostin levels drop. All this data suggests that periostin protein is involved in the formation of the meshwork structure of the PDL fibers, maintaining this structure on the bone surface. Alterations in periodontal disease and healing

Periodontal diseases are caused by bacteria acting in a preferentially susceptible host (Page and Kornman, 1997). Many inflammatory mediators and cytokines have been reported to act in this scenario, leading to loss of attachment. All these should affect the matricellular proteins that maintain the ECM and the PDL integrity. Exposure to pro-inflammatory cytokines (TNF-a) and/or microbial virulence factors (Porphyromonas gingivalis lipopolysaccharides) initially increases periostin levels in PDL fibroblasts, but chronic exposure leads to its decrease (Padial-Molina et al., 2013). During the disease process, the well-organized PDL is converted to an inflamed tissue, thereby reducing the periostin levels. Since periostin is expressed only by PDL fibroblasts, any decrease in its level

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Fig. 1.

Action of periostin in morphogenesis and maintenance of dental tissue.

reflects a loss of PDL tissue integrity. It can thus be inferred that bacterial products and inflammatory cytokines may reduce periostin levels, which may in turn compromise the structure and function of the periodontium by reducing its structural and biomechanical properties. As suggested earlier, periostin increases cell migration, recruitment, and attachment into the healing areas of different tissues. Similar mechanisms likely operate during periodontal healing. Additionally periostin regulates angiogenesis through up-regulation of matrix metalloproteinase MMP-2, which has been shown to be expressed via the avb3 integrin/extracellular related kinase (ERK) signaling pathway and vasculo-endothelial growth factor (VEGF) in human PDL cells as well (Watanabe et al., 2012). Periostin may be involved in healing after postperiodontal surgery, regenerative procedures, or even after placement of dental implants. By promoting the migration of fibroblasts (Takayama and Kudo, 2012) and osteoblasts (Horiuchi et al., 1999), periostin may play a key role in remodeling of the PDL and surrounding bone after periodontal surgery with (or without) various biomaterials used for regeneration (Fig. 1). Bone formation during mechanical loading, aided by periostin, may have direct implications for immediate functional loading of dental implants. Since no human data exists monitoring the levels of periostin in the dental tissues, it is assumed that some level should be present to maintain homeostasis and play a role during healing through various mechanisms. Further research is necessary to clarify these mechanisms. Conclusion

Periostin seems to play a fundamental role in postnatal development and repair of bone and tooth-related structures. JOURNAL OF CELLULAR PHYSIOLOGY

Expression of protein levels of periostin may help in identifying various pathways in healing and/or disease pathogenesis in the periodontium. Use of an anti-periostin antibody or recombinant periostin may be considered for therapeutic applications in dentistry. More studies are needed to confirm this hypothesis and develop treatment protocols. Acknowledgment

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