Heparan sulfate as a regulator of endochondral ossification and osteochondroma development

Abstract

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.

Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice

“…The cellular origin of osteochondoma in MHE, either from chondrocytes in the growth plate or from cells in the perichondrium, has been debated for some time (35). One reason for this debate is the difficulty of interrogating the initial phases of osteochondromagenesis using human osteochondroma specimens.…”

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries

“…A prominent example of this phenomenon can be found in members of the hedgehog family that include Sonic (Shh), Indian (Ihh) and Desert (Dhh) hedgehogs ( 11, 32,33, 34 ). The Hh proteins are very potent signaling factors and have critical functions in embryonic development as well as tissue function and homeostasis and skeletal and non-skeletal pathologies including cancer ( 4,35, 36, 37 ). Interactions with HS and HSPGs have been shown to regulate the distribution and action of Hh proteins on target cells and tissues and also their ability to form morphogen gradients within/amongst tissues during embryonic development ( 38 ).…”

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…It is encoded by an ϳ115-kb gene, HSPG2 (4,5), and is expressed in a variety of tissues, both vascular and avascular (6,7). The biological functions of perlecan span a range of processes, including cell adhesion (8,9), endocytosis (10), bone and cartilage formation (11,12), inflammation and wound healing (13,14), thrombosis (15), lipid metabolism (16), autophagy (17), tumor angiogenesis and invasiveness (18 -23), and cardiovascular development (24), where its angiogenic properties are among the most interesting. Perlecan transcription is also induced by TGF-␤ (25) and is rapidly repressed by interferon ␥ (26).…”