chondroitin-sulfates and Osteopetrosis

The primary macrophage growth factor, colony-stimulating factor-1 (CSF-1), is homodimeric and exists in 3 biologically active isoforms: a membrane-spanning, cell-surface glycoprotein (csCSF-1) and secreted glycoprotein (sgCSF-1) and proteoglycan (spCSF-1) isoforms. To investigate the in vivo role of the chondroitin sulfate glycosaminoglycan (GAG) chain of spCSF-1, we created mice that exclusively express, in a normal tissue-specific and developmental manner, either the secreted precursor of spCSF-1 or the corresponding precursor in which the GAG addition site was mutated. The reproductive, hematopoietic tooth eruption and tissue macrophage defects of CSF-1-deficient, osteopetrotic Csf1(op)/Csf1(op) mice were corrected by transgenic expression of the precursors of either sgCSF-1 or spCSF-1. Furthermore, in contrast to the transgene encoding csCSF-1, both failed to completely correct growth retardation, suggesting a role for csCSF-1 in the regulation of body weight. However, spCSF-1, in contrast to sgCSF-1, completely resolved the osteopetrotic phenotype. Furthermore, in transgenic lines expressing different concentrations of sgCSF-1 or spCSF-1, spCSF-1 more efficiently corrected Csf1(op)/Csf1(op) defects of tooth eruption, eyelid opening, macrophage morphology, and B-cell deficiency than sgCSF-1. These results indicate an important role of the CSF-1 chondroitin sulfate proteoglycan in in vivo signaling by secreted CSF-1.

Topics: Animals; B-Lymphocytes; Bone Resorption; Chondroitin Sulfates; Eyelids; Female; Gene Expression Regulation, Developmental; Growth Disorders; Hematopoiesis; Macrophage Colony-Stimulating Factor; Macrophages; Male; Mice; Mice, Mutant Strains; Mice, Transgenic; Mutation; Odontogenesis; Osteopetrosis; Phenotype; Reproduction; Tooth Eruption

Topics: Adolescent; Adult; Child; Child, Preschool; Chondroitin Sulfates; Female; Heparitin Sulfate; Humans; Infant; Male; Osteopetrosis

The organic matrix of the long bones of the "normal" rat strain and of its mutant Op/Orl were investigated. This latter strain exhibits some anomalles similar to Albers-Schönberg disease as well as tooth retentions. Bones (tibia, femur) were incubated with 14C-glucose and also submitted to a fractional extraction procedure (EDTA, urea) to separate soluble and insoluble fractions. The proteins, hexoses, hexosamines, hydroxyproline content of these fractions was determined as well as the radioactivity of the soluble extracts Glycosaminoglycans were also studied by cellogel electrophoresis after pronase digestion of the EDTA-extracts. Male and female animals of each strain were studied separately. The relative amount of soluble proteins (EDTA + urea extracts) was the same in both strains, the mineral content of the final residue was however higher in the mutant Op/Orl strain. The hydroxyproline content of the mutant-extracts were lower than in the original strain suggesting a lower soluble collagen content. This may be due to a faster polymerisation, insolubillisation of freshly synthesised collagen. The hexosamine content of the mutant urea extracts and the final residue was higher than that found in the analogous extracts obtained from the normal "normal" strain, suggesting a higher proportion of structural glycoproteins in the mutant bone, uronic acid being low or absent. Some other parameters were identical between the mutant and original strains but differed between males and females. The radioactivity of the soluble extracts was higher in the males than in females. The glycosaminoglycans of the EDTA extracts are also different: male-extracts show two bands on cellogel electrophoresis, one corresponding to chondroitin-sulphate, the other to hyaluronate. Females showed only the chondroitin sulphate band. The aminoacid composition of the insoluble residue of males was higher in basic amino acids (lysine, histidine, arginine) than the female extracts. These results indicate the existence of discrete well defined differences between the organic matrix of the orginal and mutant strain on one side and between male and female bones on the other side.

Topics: Amino Acids; Animals; Bone Matrix; Chondroitin Sulfates; Disease Models, Animal; Edetic Acid; Femur; Glycosaminoglycans; Hexosamines; Hexoses; Hyaluronic Acid; Hydroxyproline; Osteopetrosis; Proteins; Rats; Rats, Inbred Strains; Sex Factors; Tibia; Urea