heparitin-sulfate and Bone-Diseases--Metabolic

Bone remodeling is a highly coordinated process involving bone formation and resorption, and imbalance of this process results in osteoporosis. It has long been recognized that long-term heparin therapy often causes osteoporosis, suggesting that heparan sulfate (HS), the physiological counterpart of heparin, is somehow involved in bone mass regulation. The role of endogenous HS in adult bone, however, remains unclear. To determine the role of HS in bone homeostasis, we conditionally ablated Ext1, which encodes an essential glycosyltransferase for HS biosynthesis, in osteoblasts. Resultant conditional mutant mice developed severe osteopenia. Surprisingly, this phenotype is not due to impairment in bone formation but to enhancement of bone resorption. We show that osteoprotegerin (OPG), which is known as a soluble decoy receptor for RANKL, needs to be associated with the osteoblast surface in order to efficiently inhibit RANKL/RANK signaling and that HS serves as a cell surface binding partner for OPG in this context. We also show that bone mineral density is reduced in patients with multiple hereditary exostoses, a genetic bone disorder caused by heterozygous mutations of Ext1, suggesting that the mechanism revealed in this study may be relevant to low bone mass conditions in humans.

Topics: Adult; Animals; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Resorption; Cell Differentiation; Cells, Cultured; CHO Cells; Coculture Techniques; Cricetulus; Disease Models, Animal; Exostoses, Multiple Hereditary; Female; HEK293 Cells; Heparitin Sulfate; Humans; Male; Mice; Mice, Knockout; Mutagenesis, Site-Directed; Mutation; N-Acetylglucosaminyltransferases; Osteoblasts; Osteoclasts; Osteoprotegerin; Primary Cell Culture; Recombinant Proteins

Mucopolysaccharidosis (MPS) type I (alpha-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome).The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.

Topics: Adolescent; Atrophy; Bone and Bones; Bone Diseases, Metabolic; Brain; Cerebral Ventricles; Cognition Disorders; Dermatan Sulfate; Diagnosis, Differential; Female; Heparitin Sulfate; Humans; Iduronidase; Leukodystrophy, Globoid Cell; Magnetic Resonance Imaging; Mucopolysaccharidosis I; Nerve Fibers, Myelinated; Phenotype