Periostin is a member of a growing family of matricellular proteins, defined by their ability to interact with components of the extracellular milieu, and with receptors at the cell surface. Through these interactions, periostin has been shown to play a crucial role as a profibrogenic molecule during tissue morphogenesis. Tissues destined to become fibrous structures are dependent on cooperative interactions between periostin and its binding partners, whereas in its absence, these structures either totally or partially fail to become mature fibrous entities. Within the heart, fibrogenic differentiation is required for normal tissue maturation, remodeling and function, as well as in response to a pathological myocardial insult. In this review, aspects related to the function of periostin during cardiac morphogenesis, remodeling and pathology are summarized.

Periostin (PN), a novel fasciclin-related matricellular protein, has been implicated in cardiac development and postnatal remodeling, but the mechanism remains unknown. We examined the role of PN in mediating intracellular kinase activation for atrioventricular valve morphogenesis using well defined explant cultures, gene transfection systems, and Western blotting. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Functional assays with prevalvular progenitor cells showed that activating these signaling pathways promoted adhesion, migration, and anti-apoptosis. Through activation of PI3K/ERK, PN directly enhanced collagen expression. Comparing PN-null to WT mice also revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase-2 (Has2) are also enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. We also identified in valve progenitor cells a potential autocrine signaling feedback loop between PN and HA through PI3K and/or ERK. Finally, in a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent fashion. In summary, this study provides the first direct evidence that PN can act to stimulate a valvulogenic signaling pathway.