The extracellular matrix (ECM) is a highly dynamic and heterogeneous structure that plays multiple roles in living organisms. Its integrity and homeostasis are crucial for normal tissue development and organ physiology. Loss or alteration of ECM components turns towards a disease outcome. In this review, we provide a general overview of ECM components with a special focus on collagens, the most abundant and diverse ECM molecules. We discuss the different functions of the ECM including its impact on cell proliferation, migration and differentiation by highlighting the relevance of the bidirectional cross-talk between the matrix and surrounding cells. By systematically reviewing all the hereditary disorders associated to altered collagen structure or resulting in excessive collagen degradation, we point to the functional relevance of the collagen and therefore of the ECM elements for human health. Moreover, the large overlapping spectrum of clinical features of the collagen-related disorders makes in some cases the patient clinical diagnosis very difficult. A better understanding of ECM complexity and molecular mechanisms regulating the expression and functions of the various ECM elements will be fundamental to fully recognize the different clinical entities.

Skin undergoes continuous renewal throughout an individual’s lifetime relying on stem cell functionality. However, a decline of the skin regenerative potential occurs with age. The accumulation of senescent cells over time probably reduces tissue regeneration and contributes to skin aging. Keratinocytes and dermal fibroblasts undergo senescence in response to several intrinsic or extrinsic stresses, including telomere shortening, overproduction of reactive oxygen species, diet, and sunlight exposure. Epigenetic mechanisms directly regulate skin homeostasis and regeneration, but they also mark cell senescence and the natural and pathological aging processes. Progeroid syndromes represent a group of clinical and genetically heterogeneous pathologies characterized by the accelerated aging of various tissues and organs, including skin. Skin cells from progeroid patients display molecular hallmarks that mimic those associated with naturally occurring aging. Thus, investigations on progeroid syndromes strongly contribute to disclose the causal mechanisms that underlie the aging process. In the present review, we discuss the role of epigenetic pathways in skin cell regulation during physiologic and premature aging.

UV-sensitive syndrome (UV ^S S) is a recently-identified autosomal recessive disorder characterized by mild cutaneous symptoms and defective transcription-coupled repair (TC-NER), the subpathway of nucleotide excision repair (NER) that rapidly removes damage that can block progression of the transcription machinery in actively-transcribed regions of DNA. Cockayne syndrome (CS) is another genetic disorder with sun sensitivity and defective TC-NER, caused by mutations in the CSA or CSB genes. The clinical hallmarks of CS include neurological/developmental abnormalities and premature aging. UV ^S S is genetically heterogeneous, in that it appears in individuals with mutations in CSB or in a still-unidentified gene. We report the identification of a UV ^S S patient (UV ^S S1VI) with a novel mutation in the CSA gene (p.trp361cys) that confers hypersensitivity to UV light, but not to inducers of oxidative damage that are notably cytotoxic in cells from CS patients. The defect in UV ^S S1VI cells is corrected by expression of the WT CSA gene. Expression of the p.trp361cys-mutated CSA cDNA increases the resistance of cells from a CS-A patient to oxidative stress, but does not correct their UV hypersensitivity. These findings imply that some mutations in the CSA gene may interfere with the TC-NER-dependent removal of UV-induced damage without affecting its role in the oxidative stress response. The differential sensitivity toward oxidative stress might explain the difference between the range and severity of symptoms in CS and the mild manifestations in UV ^s S patients that are limited to skin photosensitivity without precocious aging or neurodegeneration.