RT Journal Article
SR Electronic
T1 A rate-limiting role for DKK1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.181404
DO 10.1124/jpet.111.181404
A1 Helmut Glantschnig
A1 Kevin Scott
A1 Richard Hampton
A1 Nan Wei
A1 Paul McCracken
A1 Pascale Nantermet
A1 Jing Zhao
A1 Salvatore Vitelli
A1 Lingyi Huang
A1 Peter Haytko
A1 Ping Lu
A1 John Fisher
A1 Punam Sandhu
A1 Jacquellynn Cook
A1 Donald Williams
A1 William Strohl
A1 Osvaldo Flores
A1 Donald Kimmel
A1 Fubao Wang
A1 An Zhiqiang
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/04/29/jpet.111.181404.abstract
AB Genetic studies have linked both osteoporotic and high bone mass (HBM) phenotypes to LDL-receptor related proteins (LRP 4/5/6). LRP are receptors for inhibitory Dickkopf-1 (DKK1) protein and treatment modalities that modulate LRP/DKK1 binding may therefore act as stimulators of bone mass accrual. Here we report that RH2-18, a fully human monoclonal anti-DKK1 antibody elicits systemic pharmacologic bone efficacy and new bone formation at endosteal bone surfaces in vivo in a mouse model of estrogen deficiency induced osteopenia. This was paralleled by partial-to-complete resolution of osteopenia (bone mineral density, BMD) at all skeletal sites investigated in femur and lumbar-vertebral bodies and the restoration of trabecular bone micro-architecture. Importantly, testing of RH2-18 in adult, osteopenic rhesus macaques demonstrated a rate limiting role of DKK1 at multiple skeletal sites and responsiveness to treatment. In conclusion, this study provides pharmacologic evidence for modulation of DKK1 bioactivity in the adult osteopenic skeleton as a viable approach to resolve osteopenia in animal models. Thus, data described here suggest that targeting DKK1 through means such as a fully-human anti-DKK1-antibody provides a potential bone-anabolic treatment for postmenopausal osteoporosis.