Periostin is a secreted extracellular matrix protein, that has been hypothesized to promote fibrogenic differentiation (Erkan et al. 2007
; Norris et al. 2008a
). In humans, periostin expression is variable in normal healthy tissues, but is most commonly associated with fibroblast-rich tissues (Tilman et al. 2007
). In this present study, we report that periostin protein is expressed in both healthy and pathological human and murine skin. Furthermore, periostin is a significant component of the granulation tissue and remodeling ECM formed during the repair of excisional dermal wounds, where periostin is associated with α-SMA myofibroblasts and keratinocytes.
In healthy human skin, periostin expression is clearly associated with keratinocytes and dermal fibroblasts (Fig. ). Interestingly, we did not detect periostin reactivity in the extracellular matrix of healthy dermis, suggesting it is unlikely abundant expression of periostin is required for maintenance of tissue homeostasis. However, the marked switch of periostin protein localization from cells to the ECM in pathological remodeling (nevus) compared to healthy skin, suggests that periostin plays a role in remodeling of tissues in response to pathological insult. Periostin expression is now known to be prevalent in many pathologies including cancer (Bao et al. 2004
; Gillan et al. 2002
; Ruan et al. 2009
; Sasaki et al. 2001
), bone marrow fibrosis (Oku et al. 2008
), and cardiac hypertrophy and remodeling (Oka et al. 2007
). In cancer, periostin has been shown to increase both cell motility (Gillan et al. 2002
) and cell survival (Bao et al. 2004
). Classed as a matricellular protein (Norris et al. 2008a
), periostin has been shown to interact with cells through αVβ3 and αVβ5 integrins (Gillan et al. 2002
), with subsequent activation of downstream targets including, but not limited to the Akt/Protein Kinase B pathways (Bao et al. 2004
). Akt/Protein Kinase B pathways are particularly associated with cell cycle progression (Yun et al. 2009
), potentially implicating ECM-associated periostin with proliferation. Interestingly, periostin has been previously shown to induce proliferation of polycystic kidney cells through αV integrins (Wallace et al. 2008
), and as proliferation of fibroblasts is an integral part of wound repair, it is possible that periostin mediates cell division. Future experiments will assess if extracellular periostin induces proliferation of dermal fibroblasts.
To further investigate the role of periostin in skin homeostasis and remodeling, we utilized the well-established excisional full thickness dermal wound repair model in mice (DiPietro et al. 1995
). Periostin protein appeared in the provisional matrix at 3 days, but was most prominent at 7 days post wounding. The appearance of periostin was concurrent with an increase in α-SMA positive fibroblasts, the cells responsible for contraction of wounds and scarring (Hinz 2007
). To our knowledge, this is the first report that periostin is associated with myofibroblasts in dermal wound repair. Previous studies have identified that periostin expression is significantly higher in keloid or hyperplastic scars compared with normal skin (Wang et al. 2007
). Furthermore, presence of periostin correlated with higher levels of transforming growth factor beta-1 (TGF-β1) in keloid scars, suggesting that periostin may be regulated by TGF-β1. Regulation of periostin by TGF-β isoforms has been confirmed in periosteum (Horiuchi et al. 1999
), periodontal ligament (Horiuchi et al. 1999
; Rios et al. 2008
), and recently in the atrioventricular valve(Norris et al. 2009
). Interestingly, differentiation of fibroblasts into myofibroblasts is also known to be regulated in part by TGF-β (Tuan et al. 1996
), opening the possibility that the expression of α-SMA and periostin occur simultaneously due to the presence of TGF-β in the wound bed. Whether periostin protein is required for myofibroblast differentiation in dermal wounds has yet to be determined, although previous studies of the atrioventricular valve identified that periostin is essential for differentiation of mesenchyme to α-SMA-containing myofibroblasts (Norris et al. 2008b
; Norris et al. 2009
Periostin reactivity in the nucleus was evident in the human keratinocytes and a subset of murine keratinocytes in healthy skin. Nuclear localization of periostin has been previously reported in carcinoma cells from a subset of patients (12%), where nuclear localization correlated with tumour size (Puglisi et al. 2008
). Whether periostin localization to the nucleus has any functional significance has not yet been determined. To date, it is known that alternate splicing of periostin results in four isoforms (Horiuchi et al. 1999
), with only isoform four actually being secreted into the ECM (Simon J. Conway, personal communication). It is possible that depending on splicing, certain isoforms are present, some which may localize with the nucleus, others with the ECM. Further experiments will investigate the expression of each isoform in healthy and pathological tissues.
In conclusion, periostin is expressed at basal levels in healthy skin, where it likely plays a role in tissue homeostasis. Furthermore, induction of ECM remodeling, whether as a result of pathological insult (nevus) or experimentally induced (punch wound) changes the localization of periostin from the intracellular to extracellular compartment. It is possible that periostin is required in the ECM, stimulating remodeling of the matrix by directly influencing cell adhesion and resulting cell behaviour. This study provides further compelling evidence that periostin functions as a matricellular protein.