▪ Abstract The heparan sulfate on the surface of all adherent cells modulates the actions of a large number of extracellular ligands. Members of both cell surface heparan sulfate proteoglycan families, the transmembrane syndecans and the glycosylphosphoinositide-linked glypicans, bind these ligands and enhance formation of their receptor-signaling complexes. These heparan sulfate proteoglycans also immobilize and regulate the turnover of ligands that act at the cell surface. The extracellular domains of these proteoglycans can be shed from the cell surface, generating soluble heparan sulfate proteoglycans that can inhibit interactions at the cell surface. Recent analyses of genetic defects in Drosophila melanogaster, mice, and humans confirm most of these activities in vivo and identify additional processes that involve cell surface heparan sulfate proteoglycans. This chapter focuses on the mechanisms underlying these activities and on the cellular functions that they regulate.

Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-κB and thereby stimulating the expression of TNF-α and macrophage inflammatory protein–2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2^–/–, and myeloid differentiation factor 88^–/– (MyD88^–/–) macrophages and completely abolished in TLR2^–/–/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-α and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-α and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.

The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term “Endometriosis” (ID:D004715) with “Etiology” (ID:Q000209), “Immunology” (ID:Q000276), “Genetics” (ID:D005823) and “Epigenesis, Genetic” (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.

Glycosaminoglycans are major constituents of the cancer cell surface and the tumor stroma. The heparan sulfate degrading enzyme heparanase, hyaluronan, and its receptor CD44 are up-regulated in breast cancer, generating a microenvironment that promotes tumor progression and metastasis. Recent experimental and clinical evidence shows that heparanase, hyaluronan, and CD44 regulate cancer cell proliferation, migration, and invasion, as well as tumor-associated angiogenesis and are correlated with patient survival. These findings suggest that they may be used as prognostic factors and targets for breast cancer treatment. (Cancer Res 2006; 66(21): 10233-7)