Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press

PERSPECTIVE

About the importance of being desulfated

Richa Khatri and Ernestina Schipani1 Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts 02114, USA

Sulfated proteoglycans have important structural and trix: fibrillar collagens, such as collagen type II and col- signaling functions in the growth plate. In the October 1, lagen type XI; sheet-forming collagen, such as collagen 2008, issue of & Development, Settembre and col- type X; and fibril-associated collagen, such as collagen leagues (pp. 2645–2650) report that lack of SUMF1, a type IX (Olsen 1996). Collagen type II is the most abun- crucial in the activation of sulfatases, causes a dant collagen, and is produced by both proliferating and severe chondrodysplasia by augmenting fibroblast early hypertrophic chondrocytes. Collagen type X is ex- growth factor signaling and by hampering the autophagic clusively expressed by hypertrophic chondrocytes. Col- process, which the investigators show is constitutively lagen type IX binds glycosaminoglycans (GAGs). GAGs on in chondrocytes. The findings highlight the essential are long repeating polymers of specific disaccharides, role of desulfation in cartilage biology and organogenesis. which are often sulfated. Proteoglycans are macromol- ecules containing a core with multiple attached GAGs (Knudson and Knudson 2001). Because of their Skeletal development depends on two mechanisms, in- high content of GAGs, proteoglycans are highly hy- tramembranous and endochondral (Karsenty and Wagner drated. One of the most important extracellular proteo- 2002; Karsenty 2003). The first, in which mesenchymal glycans is aggrecan, the predominant proteoglycan in cells develop directly into osteoblasts, is involved in the cartilage. Aggrecan forms large aggregates, which give to formation of the flat bones of the skull. The second, ac- cartilage its unique gel-like properties and its resistance counting for the development of most other bones, in- to deformation. The central component of these aggre- volves a two-stage mechanism, whereby chondrocytes gates is a long molecule of hyaluronan. Hyaluronan is form a matrix template, the growth plate, which is then the only extracellular oligosaccharide that is not cova- replaced by bone. lently linked to a protein, as it is bound to aggrecan in a During endochondral bone development, growth plate noncovalent fashion. This binding is facilitated by a link chondrocytes undergo well-ordered and controlled protein that binds to the aggrecan protein and to hyal- phases of cell proliferation, maturation, and death. Pro- uronan. The GAGs covalently attached to aggrecan are liferative chondrocytes synthesize collagen type II and keratan sulfate and chondroitin sulfate. GAGs are not form a columnar layer; they then stop proliferating and only structural components of the cartilaginous matrix, differentiate into post-mitotic hypertrophic cells. Hyper- but they also play a critical role in signaling, and some of trophic chondrocytes express predominantly collagen them are cell surface bound. In this regard, heparan sul- type X and mineralize their surrounding matrix. This fate proteoglycans (HSPGs) are particularly important unique differentiation process is followed by death of (Farah-Carson et al. 2005). HSPGs are anionic molecules hypertrophic chondrocytes, blood vessel invasion, and that consist of a protein core with covalently attached finally, replacement of the cartilaginous matrix with heparan sulfate (HS) chains of varying amounts and bone (Kronenberg 2003; Zelzer and Olsen 2003; Lefebvre lengths. HS chains are long polymers of repeating N- and Smits 2005; Provot and Schipani 2005). acetylglucosamine and uronic acid disaccharides. Each Chondrocytes are cells that produce and maintain a single disaccharide can be further modified by sulfation unique and abundant extracellular matrix. It is often by various sulfotransferases at the N,3-O or 6-O position stated that the size of an organ depends on two variables, of N-acetylglucosamine, or the 2-O position of uronic cell number and cell size. This is only partially true for acid. These modifications enable HS chains to bind nu- bone and cartilage, tissues in which matrix is as impor- merous and act as coreceptors in growth factor tant as cells (at least from a quantitative point of view). signaling. The cartilaginous matrix is formed by two components, The fibroblast growth factor (FGF) family and their the proteoglycans and the collagens. Collagens provide receptors (FGFRs) interact with cell surface HSPGs to structure and tensile strength to the matrix. There are coordinate cell-fate decisions. FGFs are a family of poly- three different types of collagens in the growth plate ma- peptides that have critical roles in cell growth, differen- tiation, survival, and development (Ornitz and Marie [Keywords: Proteoglycan; desulfation; FGF; chondrocytes] 2002). They can activate one of four high-affinity FGFRs. 1Corresponding author. E-MAIL [email protected]; FAX (617) 724-7543. The importance of FGF signaling in skeletal develop- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1735508. ment was first revealed with the discovery that a point

2750 GENES & DEVELOPMENT 22:2750–2754 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press

SUMF1 and chondrocytes mutation in the transmembrane domain of FGFR3 lead- steroid sulfates (Sardiello et al. 2005). In vertebrates, ing to its constitutive activation is the etiology of these hydrolases are associated with the turnover and Achondroplasia, one of the most common and severe degradation of molecules that are hydrolyzed in lyso- forms of dwarfism (Vajo et al. 2000). Since this discovery, somes in conjunction with acidic glycosidases. Sulfata- the etiology of many other human skeletal dysplasias ses contain a highly conserved sequence, im- has been attributed to specific mutations in the plying that they have evolved from a common ancestral encoding FGFR3. Deletion of this receptor in mice gene. They share a common mechanism of sulfate ester causes increased chondrocyte proliferation and an ex- hydrolysis in both prokaryotes and eukaryotes. In pro- panded growth plate (Ornitz and Marie 2002). Con- karyotes, sulfatases are sulfur scavengers, while in eu- versely, increased activity of FGFR3 leads to reduced karyotes they play a key role in the degradation of mol- chondrocyte proliferation and dwarfism, as in humans ecules such as GAGs. Eukaryotic sulfatases have a com- (Ornitz and Marie 2002). FGF18, a ligand produced by the mon residue as part their . This perichondrium that surrounds the growth plate, is in- residue is post-translationally converted to C␣-formyl- volved in endochondral ossification by regulating growth glycine (FGly) in the endoplasmic reticulum (ER), before plate chondrocyte proliferation, hypertrophy, and carti- the sorting of sulfatases to different cellular localiza- lage vascularization. It binds and activates FGFR3 with tions. FGly is indispensable for the catalytic activity of high affinity. This binding is facilitated by HSPGs. Upon sulfatases. binding, the receptor homodimerizes and initiates its au- The role of sulfatases in human metabolism has been tophosphorylation and stimulation of its tyrosine kinase outlined by the study of inherited diseases due to sulfa- activity. Mice that are null for FGF18 have a growth tase deficiencies, including the rare autosomal recessive plate