Anti-CHST13 monoclonal antibody Made to order

Background: Kashin-Beck disease (KBD) is an endemic osteochondropathy of unknown etiology. Osteoarthritis (OA) is a form of degenerative joint disease sharing similar clinical manifestations and pathological changes to articular cartilage with KBD. Methods: A genome-wide DNA methylation profile of articular cartilage from five KBD patients and five OA patients was first performed using the Illumina Infinium HumanMethylation450 BeadChip. Together with a previous gene expression profiling dataset comparing KBD cartilage with OA cartilage, an integrative pathway enrichment analysis of the genome-wide DNA methylation and the mRNA expression profiles conducted in articular cartilage was performed by InCroMAP software. Results: We identified 241 common genes altered in both the DNA methylation profile and the mRNA expression profile of articular cartilage of KBD versus OA, including CHST13 (NM_152889, fold-change = 0.5979, P-methy = 0.0430), TGFBR1 (NM_004612, fold-change = 2.077, P-methy = 0.0430), TGFBR2 (NM_001024847, fold-change = 1.543, P-methy = 0.037), TGFBR3 (NM_001276, fold-change = 0.4515, P-methy = 6.04 x 10(-4)), and ADAM12 (NM_021641, fold-change = 1.9768, P-methy = 0.0178). Integrative pathway enrichment analysis identified 19 significant KEGG pathways, including mTOR signaling (P = 0.0301), glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate (P = 0.0391), glycosaminoglycan biosynthesis-keratan sulfate (P = 0.0278), and PI3K-Akt signaling (P = 0.0243). Conclusion: This study identified different molecular features between Kashin-Beck disease and primary osteoarthritis and provided novel clues for clarifying the pathogenetic differences between KBD and OA.

Chondroitin/dermatan sulfate (CS/DS) proteoglycans consist of unbranched sulfated polysaccharide chains of repeating GalNAc-GlcA/IdoA disaccharide units, attached to serine residues on specific proteins. The CS/DS proteoglycans are abundant in the extracellular matrix where they have essential functions in tissue development and homeostasis. In this report a phylogenetic analysis of vertebrate genes coding for the enzymes that modify CS/DS is presented. We identify single orthologous genes in the zebrafish genome for the sulfotransferases chst7, chst11, chst13, chst14, chst15 and ust and the epimerase dse. In contrast, two copies were found for mammalian sulfotransferases CHST3 and CHST12 and the epimerase DSEL, named chst3a and chst3b, chst12a and chst12b, dsela and dselb, respectively. Expression of CS/DS modification enzymes is spatially and temporally regulated with a large variation between different genes. We found that CS/DS 4-O-sulfotransferases and 6-O-sulfotransferases as well as CS/DS epimerases show a strong and partly overlapping expression, whereas the expression is restricted for enzymes with ability to synthesize di-sulfated disaccharides. A structural analysis further showed that CS/DS sulfation increases during embryonic development mainly due to synthesis of 4-O-sulfated GalNAc while the proportion of 6-O-sulfated GalNAc increases in later developmental stages. Di-sulfated GalNAc synthesized by Chst15 and 2-O-sulfated GlcA/IdoA synthesized by Ust are rare, in accordance with the restricted expression of these enzymes. We also compared CS/DS composition with that of heparan sulfate (HS). Notably, CS/DS biosynthesis in early zebrafish development is more dynamic than HS biosynthesis. Furthermore, HS contains disaccharides with more than one sulfate group, which are virtually absent in CS/DS.