Periostin is a fibrogenic protein that mediates fibroblast differentiation and extracellular matrix synthesis. Here, we show that periostin is dynamically and temporally expressed during skin development, is induced by TGF-beta1 in vitro and is significantly upregulated during wound repair as well as cutaneous pathologies.

Epidermal tissue repair represents a complex series of temporal and dynamic events resulting in wound closure. Matricellular proteins, not normally expressed in quiescent adult tissues, play a pivotal role in wound repair and associated extracellular matrix remodeling by modulating the adhesion, migration, intracellular signaling, and gene expression of inflammatory cells, pericytes, fibroblasts and keratinocytes. Several matricellular proteins show temporal expression during dermal wound repair, but the expression pattern of the recently identified matricellular protein, periostin, has not yet been characterized. The primary aim of this study was to assess whether periostin protein is present in healthy human skin or in pathological remodeling (Nevus). The second aim was to determine if periostin is expressed during dermal wound repair. Using immunohistochemistry, periostin reactivity was detected in the keratinocytes, basal lamina, and dermal fibroblasts in healthy human skin. In pathological nevus samples, periostin was present in the extracellular matrix. In excisional wounds in mice, periostin protein was first detected in the granulation tissue at day 3, with levels peaking at day 7. Periostin protein co-localized with α-smooth muscle actin-positive cells and keratinocytes, but not CD68 positive inflammatory cells. We conclude that periostin is normally expressed at the cellular level in human and murine skin, but additionally becomes extracellular during tissue remodeling. Periostin may represent a new therapeutic target for modulating the wound repair process.

Recently identified as a key component of the murine periodontal ligament (PDL), periostin has been implicated in the regulation of collagen fibrillogenesis and fibroblast differentiation. We investigated whether periostin protein is expressed in the human PDL in situ and the mechanisms regulating periostin expression in PDL fibroblasts in vitro. With immunohistochemistry, periostin protein was identified in the PDL, with expression lower in teeth with reduced occlusal loading. In vitro application of uniaxial cyclic strain to PDL fibroblasts elevated periostin mRNA levels, depending on the age of the patient. Treatment with transforming growth factor-beta1 (TGF-β1) also significantly increased periostin mRNA levels, an effect attenuated by focal adhesion kinase (FAK) inhibition. FAK-null fibroblasts contained no detectable periostin mRNA, even after stimulation with cyclic strain. In conclusion, periostin protein is strongly expressed in the human PDL. In vitro, periostin mRNA levels are modulated by cyclic strain as well as TGF-β1 via FAK-dependent pathways.

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The mechanism by which mutated copper-zinc superoxide dismutase (SOD1) causes familial amyotrophic lateral sclerosis is believed to involve an adverse gain of function, independent of the physiological antioxidant enzymatic properties of SOD1. In this study, we have observed that mutant SOD1 (G41S, G85A, and G93A) but not the wild type significantly reduced the stability of the low molecular weight neurofilament mRNA in a dosage-dependent manner. We have also demonstrated that mutant SOD1 but not the wild type bound directly to the neurofilament mRNA 3-untranslated region and that the binding was necessary to induce mRNA destabilization. These observations provide an explanation for a novel gain of function in which mutant SOD1 expression in motor neurons alters an intermediate filament protein expression. Copper-zinc superoxide dismutase (SOD1)1 is a small and abundant intracellular metalloenzyme that catalyzes the conversion of the superoxide anion to hydrogen peroxide (1, 2). The demonstration of a genetic linkage between mutations in the SOD1 gene and familial amyotrophic lateral sclerosis aroused interest in the role of SOD1 in motor neuron death (3). The mechanisms by which mutations in the SOD1 gene contribute to the pathogenesis of ALS remain to be defined crisply. A gain of function to the SOD1 enzyme, conferred by the mutation, remains a potential mechanism for this toxicity. Supporting this concept are the observations that many SOD1 mutants maintain normal enzymatic function (4), that SOD1 knock-out mice do not develop an ALS-like phenotype (5), and that the over-expression of wild type (WT) SOD1 in mutant SOD1 transgenic mouse models does not modify the disease state (5). A mechanism reported recently (6) for the underlying mutant SOD1 toxicity proposes that the formation of the monomeric mutant SOD1 protein is the result of oxidative stress, which leads to microaggregate formation. It was also shown that SOD1 G93A but not WT co-localizes with neurofilamentous aggregates induced by low molecular weight neurofilament (NFL) overexpression in transfected Neuro2A cells (7). Neuropathological hallmarks of ALS include the degeneration of the descending corticospinal tracts and spinal, bulbar, and cortical motor neurons (8). In the latter nerves, degenerating neurons characteristically contain a variety of inclusions, including neurofilamentous aggregates. Such neurofilamentous aggregates have been observed in a number of transgenic mouse models of motor neuron degeneration in which the stoichiometry of expression of the individual neurofilament (NF) subunits has been altered. These include alterations in the level of expression of each of the neurofilament subunit proteins (NFL and middle and high molecular weight neurofilaments) (9 -11) and related intermediate filament proteins (12). It has been shown previously (13-15) by both in situ hybridization and single cell RT-PCR that the level of expression of NFL mRNA is reduced selectively in degenerating spinal motor neurons in ALS, suggesting that the alte...