transforming-growth-factor-beta and Osteopetrosis

Sclerosing bone disorders are caused by impaired osteoclastic bone resorption or increased bone formation. Osteopetrosis, a representative disease caused by impaired bone resorption, is a heterogeneous disease, and various molecules have been recently identified to be responsible. In infantile malignant osteopetrosis, there are osteoclast-rich and osteoclast-poor forms, which are caused by dysfunction of osteoclasts and impaired osteoclastogenesis, respectively. As to the sclerosing bone diseases related to the increased bone formation, molecular analyses of these disorders uncovered the involvement of TGF-beta and Wnt signaling in the regulation of bone mass.

Topics: Bone Resorption; Camurati-Engelmann Syndrome; Dysostoses; Genes, Dominant; Genes, Recessive; Humans; Hyperostosis; Osteoclasts; Osteogenesis; Osteopetrosis; Signal Transduction; Transforming Growth Factor beta; Wnt Proteins

The study gives a further biochemical description of two different forms of autosomal dominant osteopetrosis (ADO) in relation to murine counterparts, with special attention to osteoblast function and the recent discovery of LRP5 gene mutations in ADO I. Patients and controls were investigated for markers of bone formation and resorption at baseline and following stimulation with thyroid hormone. Moreover, four different well-described murine models of osteopetrosis were investigated. Concerning the human forms, serum TSH levels decreased in all subjects, indicating effects on the target tissue. Osteocalcin and cross-linked collagen (NTx) were without significant differences among the groups. Significant increases in both markers were seen following stimulation. Baseline active TGF-beta1 levels were increased in both types of ADO (60% in ADO I [P = 0.006]; 46% in ADO II [P = 0.001], respectively), whereas fibronectin levels were decreased in both (ADO I 58% and ADO II 63% of normal, respectively [P = 0.012 and P = 0.001]). Following treatment, levels increased temporarily in all groups. In the murine models, active TGF-beta1 was significantly decreased in the tl- and ia-rat, whereas fibronectin levels were decreased in the mi-mouse, however, increased in the ia-rat. In conclusion, both types of ADO showed the same qualitative biochemical differences compared to controls, except that OPG levels were higher in ADO I. The decreased fibronectin levels in both types and in murine models reflect decreased bone resorption; however, this may also indicate hitherto unrecognized alterations in bone formation. Biochemical differences among known syndromes related to mutations in the LRP5 gene indicate different underlying pathogenetic mechanisms.

Topics: Adult; Animals; Bone and Bones; Collagen; Disease Models, Animal; Female; Fibronectins; Genes, Dominant; Glioma; Hemoglobin M; Humans; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Male; Mice; Middle Aged; Mutation; Osteocalcin; Osteopetrosis; Rats; Receptors, LDL; Syndrome; Thyroid Hormones; Time Factors; Transforming Growth Factor beta

Congenital osteopetrosis in mammals is an inherited bone disease caused by aberrations in osteoclast development and/or function. Colony-stimulating factor-1 (CSF-1) promotes formation of osteoclasts and is produced by osteoblasts. Recently, two osteopetrotic mutations (op mouse and tl rat) have been shown to have reductions in CSF-1 activity, and CSF-1 injections improve the skeletal manifestations in each. Several different CSF-1 transcripts have been described in mouse and human soft tissues, and differential expression of CSF-1 transcripts has been documented. Thus, we compared gene expression for CSF-1 as reflected by mRNA levels in the bones of tl rats and op mice, and also two other osteopetrotic rat mutations (ia and op). In op mouse calvaria the 4.6 kb transcript was reduced while the 2.3 kb transcript was absent. However, no differences were detected in the levels of these transcripts in mutant and normal calvaria of tl stock. In contrast, CSF-1 transcript levels were elevated in op rat mutants and variable in ia mutants compared to normal littermates. Osteoblast cultures derived from neonatal animals of tl and op rat stock showed the same differences seen in calvarial bone in vivo. The mRNA expression of another growth factor, TGF-beta 1, paralleled that of CSF-1 in vivo and in vitro in the rat mutations. These data demonstrate the emerging molecular heterogeneity among osteopetrotic mutations and underscore the need to evaluate the contributions of these and other cytokines to osteoclast differentiation and function in each mutation.

Topics: Animals; Bone and Bones; Cells, Cultured; Gene Expression; Macrophage Colony-Stimulating Factor; Mice; Mice, Mutant Strains; Mutation; Osteoblasts; Osteopetrosis; Rats; Rats, Mutant Strains; Reference Values; RNA, Messenger; Skull; Transforming Growth Factor beta