Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) de Show more
Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression. To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1 All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1 A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression. Show less
Multiple osteochondromas (MO) syndrome is a dominant autosomal bone disorder characterized by the formation of cartilage-capped bony outgrowths that develop at the juxtaposition of the growth plate of Show more
Multiple osteochondromas (MO) syndrome is a dominant autosomal bone disorder characterized by the formation of cartilage-capped bony outgrowths that develop at the juxtaposition of the growth plate of endochondral bones. MO has been linked to mutations in either EXT1 or EXT2, two glycosyltransferases required for the synthesis of heparan sulfate (HS). The establishment of mouse mutants demonstrated that a clonal, homozygous loss of Ext1 in a wild type background leads to the development of osteochondromas. Here we investigate mechanisms that might contribute to the variation in the severity of the disease observed in human patients. Our results show that residual amounts of HS are sufficient to prevent the development of osteochondromas strongly supporting that loss of heterozygosity is required for osteochondroma formation. Furthermore, we demonstrate that different signaling pathways affect size and frequency of the osteochondromas thereby modulating the severity of the disease. Reduced Fgfr3 signaling, which regulates proliferation and differentiation of chondrocytes, increases osteochondroma number, while activated Fgfr3 signaling reduces osteochondroma size. Both, activation and reduction of Wnt/β-catenin signaling decrease osteochondroma size and frequency by interfering with the chondrogenic fate of the mutant cells. Reduced Ihh signaling does not change the development of the osteochondromas, while elevated Ihh signaling increases the cellularity and inhibits chondrocyte differentiation in a subset of osteochondromas and might thus predispose osteochondromas to the transformation into chondrosarcomas. Show less
Most elements of the vertebrate skeleton are formed by endochondral ossification. This process is initiated with mesenchymal cells that condense and differentiate into chondrocytes. These undergo seve Show more
Most elements of the vertebrate skeleton are formed by endochondral ossification. This process is initiated with mesenchymal cells that condense and differentiate into chondrocytes. These undergo several steps of differentiation from proliferating into hypertrophic chondrocytes, which are subsequently replaced by bone. Chondrocyte proliferation and differentiation are tightly controlled by a complex network of signaling molecules. During recent years, it has become increasingly clear that heparan sulfate (HS) carrying proteoglycans play a critical role in controlling the distribution and activity of these secreted factors. In this review we summarize the current understanding of the role of HS in regulating bone formation. In human, mutations in the HS synthetizing enzymes Ext1 and Ext2 induce the Multiple Osteochondroma syndrome, a skeletal disorder characterized by short stature and the formation of benign cartilage-capped tumors. We review the current insight into the origin of the disease and discuss its possible molecular basis. In addition, we summarize the existing insight into the role of HS as a regulator of signal propagation and signaling strength in the developing skeleton. Show less
Most elements of the vertebrate skeleton are formed by endochondral ossification. This process is initiated with mesenchymal cells that condense and differentiate into chondrocytes. These undergo seve Show more
Most elements of the vertebrate skeleton are formed by endochondral ossification. This process is initiated with mesenchymal cells that condense and differentiate into chondrocytes. These undergo several steps of differentiation from proliferating into hypertrophic chondrocytes, which are subsequently replaced by bone. Chondrocyte proliferation and differentiation are tightly controlled by a complex network of signaling molecules. During recent years, it has become increasingly clear that heparan sulfate (HS) carrying proteoglycans play a critical role in controlling the distribution and activity of these secreted factors. In this review we summarize the current understanding of the role of HS in regulating bone formation. In human, mutations in the HS synthetizing enzymes Ext1 and Ext2 induce the Multiple Osteochondroma syndrome, a skeletal disorder characterized by short stature and the formation of benign cartilage-capped tumors. We review the current insight into the origin of the disease and discuss its possible molecular basis. In addition, we summarize the existing insight into the role of HS as a regulator of signal propagation and signaling strength in the developing skeleton. Show less