Extracellular sulfatases support cartilage homeostasis by regulating BMP and FGF signaling pathways

Abstract

The balance between anabolic and catabolic signaling pathways is critical in maintaining cartilage homeostasis and its disturbance contributes to joint diseases such as osteoarthritis (OA). A unique mechanism that modulates the activity of cell signaling pathways is controlled by extracellular heparan endosulfatases Sulf-1 and Sulf-2 (Sulfs) that are overexpressed in OA cartilage. This study addressed the role of Sulfs in cartilage homeostasis and in regulating bone morphogenetic protein (BMP)/Smad and fibroblast growth factor (FGF)/Erk signaling in articular cartilage. Spontaneous cartilage degeneration and surgically induced OA were significantly more severe in Sulf-1 −/− and Sulf-2 −/− mice compared with wild-type mice. MMP-13, ADAMTS-5, and the BMP antagonist noggin were elevated whereas col2a1 and aggrecan were reduced in cartilage and chondrocytes from Sulf −/− mice. Articular cartilage and cultured chondrocytes from Sulf −/− mice showed reduced Smad1 protein expression and Smad1/5 phosphorylation, whereas Erk1/2 phosphorylation was increased. In human chondrocytes, Sulfs siRNA reduced Smad phosphorylation but enhanced FGF-2-induced Erk1/2 signaling. These findings suggest that Sulfs simultaneously enhance BMP but inhibit FGF signaling in chondrocytes and maintain cartilage homeostasis. Approaches to correct abnormal Sulf expression have the potential to protect against cartilage degradation and promote cartilage repair in OA.artilage homeostasis is controlled by extracellular factors such as mechanical loading, cytokines, and growth factors that are translated by intracellular signaling pathways to changes in cell survival, activation, and differentiation. Abnormal activation of these signaling pathways during development results in skeletal dysplasias and, in mature joints, leads to osteoarthritis (OA) (1).Bone morphogenetic proteins (BMPs) regulate various stages of cartilage and bone development (2-4), promote chondrogenesis from mesenchymal stem cells, and stimulate cartilage repair (5-7). BMPs bind and signal through serine/threonine kinase receptors (8-10). BMP-7 binding to the BMP receptor type IB leads to receptor dimerization so that the type I receptor phosphorylates Smad1/5/8 and stimulates expression of genes that promote cartilage repair (7, 11) and may protect against OA (6, 12). The BMP antagonist noggin is a secreted protein that interacts with heparan sulfate proteoglycans (HSPGs) at the cell membrane where it binds and prevents BMP-2, -4, -6, and -7 from activating their receptors (13).In contrast, fibroblast growth factor-2 (FGF-2) stimulates catabolic responses in chondrocytes by activating Erk1/2 (14). Models have been proposed to describe the interaction of HSPGs with FGFs and their receptors, yet the precise molecular details remain to be determined (15). It has been established that FGF signaling requires HSPGs to form stable ligand/receptor complexes, apparently by protecting the FGF ligand from proteolytic degradation and by enhancing and stabilizing cell surface ligand/receptor ...

The extracellular matrix molecule tenascin C modulates expression levels and territories of key patterning genes during spinal cord astrocyte specification

“…S4B). Both genes directly intervene in FGF signalling (Buono et al, 2010;Otsuki et al, 2010). Moreover, we identified several genes that are involved in neural patterning during spinal cord development (supplementary material Fig.…”

“…Furthermore, Sulf1 influences both FGF and bone morphogenetic protein (BMP) signalling (Lamanna et al, 2008;Otsuki et al, 2010). Thus, we hypothesized that the increased Sulf1 expression in the Tnc-deficient spinal cord may lead to alterations in growth factor responsiveness.…”

“…Both molecules promote Shh signalling in the developing ventral spinal cord (Danesin et al, 2006;Martinez-Morales et al, 1997). Sulf1 also negatively regulates FGF signalling (Lamanna et al, 2008;Otsuki et al, 2010). Low FGF-signalling levels during early forebrain development lead to proliferation of NPCs, whereas high levels lead to an upregulation of the EGFR and consequently to the onset of gliogenesis (Lillien and Raphael, 2000;Qian et al, 1997;Temple, 2001).…”

Sulf1 and Sulf2 expression in the nervous system and its role in limiting neurite outgrowth in vitro

“…The sulphation pattern of HSPGs is critical for this function (Pellegrini, 2001) and is regulated by a novel class of endosulphatases, Sulf1 and Sulf2, that cleave 6-Osulphate groups from heparan sulphate chains (Morimoto-Tomita et al, 2002;Uchimura et al, 2006). Altering the activity of Sulf1 and Sulf2 has been shown to affect Wnt, FGF, VEGF, BMP and GDNF signalling (Ai et al, 2003;Ai et al, 2007;Dhoot et al, 2001;Higginson et al, 2012;Otsuki et al, 2010;Sahota and Dhoot, 2009;Tran et al, 2012;Uchimura et al, 2006). In neurons, Sulf1 and Sulf2 have been reported to facilitate binding of GDNF to its receptor RET by inhibiting the binding of GDNF to HSPGs (Ai et al, 2007).…”

Attachment ofChlamydia trachomatisL2 to host cells requires sulfation

“…Lacrimal gland development (17), viability and neural development in C. elegans (18), FGF-induced signaling (19), and cartilage homeostasis (20) all depend on sulfation. Sulfation of tyrosine residues is important for the interaction of chemokines and their receptors (21)(22)(23) and for binding and entry of HIV (24).…”