Serum levels of TGF-beta and fibronectin in autosomal dominant osteopetrosis in relation to underlying mutations and well-described murine counterparts.

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.