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.