Sclerostin attenuates the mechanical loading response in trabecular bone

Osteocytes play a major role in normal bone maintenance and have recently been implicated in a number of conditions that affect bone. Sclerostin is an osteocyte secreted protein, deficiency of which was found to be causative of the high bone mass phenotype in patients with sclerosteosis and van Buchem's disease. Mechanical loading of bone within the anabolic range decreases osteocyte sclerostin expression. An anti-sclerostin antibody, currently undergoing clinical trials, has been developed as a bone anabolic agent. Recent evidence from in vitro and in vivo experiments shows that osteocytes, via sclerostin, downregulate osteoblastogenesis (anti-anabolic) and potentiate osteoclastogenesis procatabolic) activity. PURPOSE OF STUDY In this study, the interaction between sclerostin and mechanical loading was investigated in bovine trabecular bone cores cultured ex vivo. METHODS Using a novel bone organ culture system, fresh bovine trabecular bone cores were cultured for up to 3 weeks. The cores were divided into 3 groups; A (loaded, using the Zetos™ piezoelectric loading system), which were subjected to daily mechanical loading (300 cycles of 4,000 μstrain at 1 Hz), B (loaded + sclerostin), which had an identical loading regime and were perfused continuously with 50 ng/ml recombinant human sclerostin, and C (unloaded), which were not loaded and were perfused with medium in the absence of sclerostin. Daily measurements of stiffness, pH and ionic calcium were made. Calcein was introduced both one week and one day before the experiment was ended. RESULTS The stiffness of the cores increased in response to mechanical loading in A. Samples in B had a significantly lower response to mechanical loading. The pH of medium from both B and C was significantly lower than that from A. The ionic calcium concentration present in the culture media after 24 hours was higher in B than in A. Calcein uptake in B was also observed to be less than in A. CONCLUSIONS This is the first direct evidence that sclerostin blunts the anabolic effect of mechanical loading via reduced bone formation, which is in agreement with current in vitro and in vivo published work. The ex vivo culture of trabecular bone appears to be an ideal model for the demonstration of direct effects of bone acting agents in large mammals