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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.181404.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- hPTH
- human parathyroid hormone fragment
- aBMD
- areal bone mineral density
- BMD
- bone mineral density
- BV/TV
- bone volume per tissue volume
- CT
- computed tomography
- DKK1
- Dickkopf-1
- DXA
- dual-energy X-ray absorptiometry
- HBM
- high bone mass
- HR-pQCT
- high-resolution peripheral quantitative computed tomography
- LRP
- low-density lipoprotein receptor-related protein
- MAR
- mineral apposition rate
- MS/BS
- mineralizing surface/bone surface
- OVX
- ovariectomized
- PBST
- phosphate-buffered saline with 0.05% Tween 20
- QCT
- quantitative computed tomography
- CTx
- cross-linked C telopeptide of collagen type I
- sCTx
- serum CTx
- TbN
- trabecular number
- TbSp
- trabecular separation
- TbTh
- trabecular thickness
- TbvBMD
- trabecular volumetric bone mineral density
- NTx
- N-telopeptides
- uNTx
- urinary NTx
- vBMD
- volumetric bone mineral density
- rhDKK1
- recombinant human DKK1
- P1NP
- procollagen type 1 NH2-terminal propeptide
- TBS
- Tris-buffered saline.
- Received March 11, 2011.
- Accepted April 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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