Periostin Responds to Mechanical Stress and Tension by Activating the MTOR Signaling Pathway

Abstract

Current knowledge about Periostin biology has expanded from its recognized functions in embryogenesis and bone metabolism to its roles in tissue repair and remodeling and its clinical implications in cancer. Emerging evidence suggests that Periostin plays a critical role in the mechanism of wound healing; however, the paracrine effect of Periostin in epithelial cell biology is still poorly understood. We found that epithelial cells are capable of producing endogenous Periostin that, unlike mesenchymal cell, cannot be secreted. Epithelial cells responded to Periostin paracrine stimuli by enhancing cellular migration and proliferation and by activating the mTOR signaling pathway. Interestingly, biomechanical stimulation of epithelial cells, which simulates tension forces that occur during initial steps of tissue healing, induced Periostin production and mTOR activation. The molecular association of Periostin and mTOR signaling was further dissected by administering rapamycin, a selective pharmacological inhibitor of mTOR, and by disruption of Raptor and Rictor scaffold proteins implicated in the regulation of mTORC1 and mTORC2 complex assembly. Both strategies resulted in ablation of Periostin-induced mitogenic and migratory activity. These results indicate that Periostin-induced epithelial migration and proliferation requires mTOR signaling. Collectively, our findings identify Periostin as a mechanical stress responsive molecule that is primarily secreted by fibroblasts during wound healing and expressed endogenously in epithelial cells resulting in the control of cellular physiology through a mechanism mediated by the mTOR signaling cascade.

Preliminary insight into the periostin leverage during periodontal tissue healing

“…At the gingival epithelial level, periostin promotes an increased proliferation and migration rate similar to that observed in skin epithelial cells as a potential enhancer of wound closure after injury (Rosselli‐Murai et al. ). Similarly, epithelial cells, as the first front of defence in periodontal tissues, increase periostin release to promote gingival sealing around the teeth in response to bacteria.…”

“…Moreover, periostin activates the cell survival AKT/PKB/mTOR pathway (Rosselli‐Murai et al. , Padial‐Molina et al. ) and induces migration and proliferation through the interaction with α v β 3 and α v β 5‐integrins (Li et al.…”

“…Its association with the α v ß 3 integrin receptor has been found to support AKT/PKB signalling, increasing fibroblast and epithelial/endothelial migration as well as activating the mTOR signalling pathway leading to proliferation (Rosselli‐Murai et al. , Padial‐Molina et al. ).…”

“…In addition, periostin has been found to possess potent mitogenic properties via integrin receptor interactions. Its association with the a v ß 3 integrin receptor has been found to support AKT/PKB signalling, increasing fibroblast and epithelial/endothelial migration as well as activating the mTOR signalling pathway leading to proliferation (Rosselli-Murai et al 2013). Similar to other highly homologous proteins such as bigH3, periostin expression is regulated by TGF-ß in response to mechanical stimulation (Rios et al 2008).…”

PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells

“…Knockdown of Raptor and Rictor was performed as previously described [70–72]. In detail, cells were seeded in 24-well plates and transfected with HiPerFect (Qiagen) using 15 nM double-stranded RNA oligonucleotides directed against human Raptor (forward: 5′- GGA CAA CGG CCA CAA GUAdTdT-3′ and reverse: 5′- UAC UUG UGG CCG UUG UCCdTdT-3′), or 5 nM double-stranded RNA oligonucleotides against Rictor (forward: 5′- CCU AAU GAA UAU GGC UGC AUC CUU UdTdT-3′ and reverse: 5′- AAA GGA UGC AGC CAU AUU CAU UAG GdTdT-3′) (Invitrogen).…”