Response to Letter Regarding Article, “Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr(−/−) Mice”
We appreciate the analysis put forward by Secchiero and Zauli and agree with their view that in vivo inhibition of vascular calcification by Fc osteoprotegerin (Fc-OPG) is unlikely to be mediated through tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Although we originally acknowledged TRAIL as a possible alternative mediator of Fc-OPG effects, Secchiero and Zuli correctly note that, given the antiatherosclerotic effects of TRAIL,1 the lack of effect of Fc-OPG on atherosclerosis in our study2 suggests that Fc-OPG is acting on vascular calcification independently of TRAIL.
As further evidence against a TRAIL-mediated mechanism, Secchiero and Zauli also suggest that truncated Fc-OPG may have low binding affinity for TRAIL. Although such a finding would strengthen our hypothesis, we have not found evidence for it in the literature or in the cited report.3 Indeed, 1 group has reported that truncated Fc-OPG does inhibit TRAIL function,4 and a preliminary report indicates that its binding affinity for TRAIL may be comparable to that of the endogenous receptor.5
Whether elevated OPG levels are a cause or consequence of clinical atherosclerosis remains in question. Since Fc-OPG treatment did not promote atherosclerosis in our mice, our results favor the latter hypothesis. Is it possible that native OPG has an atherogenic effect not seen with Fc-OPG? It’s unlikely, but we cannot exclude the possibility.
Dr Morony, Dr Cattley, G. Van, D. Dwyer, Dr Stolina, and Dr Kostenuik are employees and stockholders of Amgen Inc. The other authors report no conflicts.
Secchiero P, Candido R, Corallini F, Zacchigna S, Toffoli B, Rimondi E, Fabris B, Giacca M, Zauli G. Systemic tumor necrosis factor–related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein e-null diabetic mice. Circulation. 2006; 114: 1522–1530.
Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, Stolina M, Kostenuik PJ, Demer LL. Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(−/−) mice. Circulation. 2008; 117: 411–420.
Schneeweis LA, Willard D, Milla ME. Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kB ligand. J Biol Chem. 2005; 280: 41155–41164.
Fisher JL, Thomas-Mudge RJ, Elliott J, Hards DK, Sims NA, Slavin J, Martin TJ, Gillespie MT. Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res. 2006; 66: 3620–3628.
Elliott R, Kostenuik P, Chen C, Kelley M, Hawkins N, Housman J, McCab S, Mukku V, Sullivan J, Dougall W. Denosumab is a selective inhibitor of human receptor activator of NF-κB ligand that blocks osteoclast formation in vitro and in vivo. Eur J Cancer Suppl. 2006; 4: 62.