title: A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody.
abstract: Genetic studies have linked both osteoporotic and high bone mass phenotypes to low-density lipoprotein receptor-related proteins (LRP4, LRP5, and LRP6). LRPs are receptors for inhibitory Dickkopf-1 (DKK1) protein, and treatment modalities that modulate LRP/DKK1 binding therefore may 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) at all of the skeletal sites investigated in femur and lumbar-vertebral bodies and the restoration of trabecular bone microarchitecture. More 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 the 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.
authors.affiliation: Bone Biology, Merck Research Laboratories, 700 Sumneytown Pike, WP26A-1000, West Point, PA 19486, USA. helmut_glantschnig@merck.com
authors.forename: Helmut
authors.initials: H
authors.lastname: Glantschnig
authors.forename: Kevin
authors.initials: K
authors.lastname: Scott
authors.forename: Richard
authors.initials: R
authors.lastname: Hampton
authors.forename: Nan
authors.initials: N
authors.lastname: Wei
authors.forename: Paul
authors.initials: P
authors.lastname: McCracken
authors.forename: Pascale
authors.initials: P
authors.lastname: Nantermet
authors.forename: Jing Z
authors.initials: JZ
authors.lastname: Zhao
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vitelli
authors.forename: Lingyi
authors.initials: L
authors.lastname: Huang
authors.forename: Peter
authors.initials: P
authors.lastname: Haytko
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: John E
authors.initials: JE
authors.lastname: Fisher
authors.forename: Punam
authors.initials: P
authors.lastname: Sandhu
authors.forename: Jacquelynn
authors.initials: J
authors.lastname: Cook
authors.forename: Donald
authors.initials: D
authors.lastname: Williams
authors.forename: William
authors.initials: W
authors.lastname: Strohl
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Flores
authors.forename: Donald
authors.initials: D
authors.lastname: Kimmel
authors.forename: Fubao
authors.initials: F
authors.lastname: Wang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015519:Bone Density / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000276:immunology*; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins