Proteoglycans in health and disease: the multiple roles of syndecan shedding

Abstract

Proteolytic processes in the extracellular matrix are a major influence on cell adhesion, migration, survival, differentiation and proliferation. The syndecan cell‐surface proteoglycans are important mediators of cell spreading on extracellular matrix and respond to growth factors and other biologically active polypeptides. The ectodomain of each syndecan is constitutively shed from many cultured cells, but is accelerated in response to wound healing and diverse pathophysiological events. Ectodomain shedding is an important regulatory mechanism, because it rapidly changes surface receptor dynamics and generates soluble ectodomains that can function as paracrine or autocrine effectors, or competitive inhibitors. It is known that the family of syndecans can be shed by a variety of matrix proteinase, including many metzincins. Shedding is particularly active in proliferating and invasive cells, such as cancer cells, where cell‐surface components are continually released. Here, recent research into the shedding of syndecans and its physiological relevance are assessed.

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…Syndecan shedding is highly regulated and dependent on the so-called sheddase enzymes. 188 In Paper I and II, we showed that inhibition of NF-κB reduced syndecan-4 shedding from cardiac myocytes and fibroblasts.…”

Soluble Syndecan-1: Does This Biomarker Address a Seemingly Insoluble Problem in Inflammatory Bowel Disease?

“…Changes in expression and function of these molecules are associated with and contribute to many pathophysiological conditions including malignancies and inflammation [1,2]. Syndecans are composed of a core protein comprised of an ectodomain, a transmembrane domain, and a conserved cytoplasmic domain, with three or more structurally diverse heparan sulfate chains.…”

“…Syndecans are composed of a core protein comprised of an ectodomain, a transmembrane domain, and a conserved cytoplasmic domain, with three or more structurally diverse heparan sulfate chains. Four individual syndecans are expressed in a highly regulated tissue-, cell-, and development-specific manner [1,2]. As part of normal cell HSPG turnover, the intact ectodomain is shed from the cell surface, rendering HSPG soluble.…”

“…Syndecan shedding occurs by highly regulated cleavage mechanisms in response to specific developmental and homeostatic signals, but also in response to pathophysiological signals such as inflammatory cytokines and chemokines, as illustrated in Fig. 1 [2,3]. Of the four identified syndecans, syndecan-1 is predominantly expressed by plasma cells and mucosal epithelial cells, such as intestinal epithelial cells [3].…”

“…Of the four identified syndecans, syndecan-1 is predominantly expressed by plasma cells and mucosal epithelial cells, such as intestinal epithelial cells [3]. Syndecan expression and shedding is highly modulated in inflammation-associated disease states, such as Crohn's disease or ulcerative colitis [1][2][3].…”