RS-66271, a C-terminally substituted analog of human parathyroid hormone-related protein (1-34), increases trabecular and cortical bone in ovariectomized, osteopenic rats.
It was predicted from the amino acid sequence of the bone anabolic peptides, parathyroid hormone (PTH) (1-34) and PTH related protein (PTHrP) (1-34), that the C-terminal amino acids form an amphipathic alpha-helix. Therefore, we substituted a model amphipathic alpha-helical peptide (MAP) sequence in the C-terminal region of hPTHrP(1-34), obtaining RS-66271 ([MAP1-10]22-31 hPTHrP(1-34)-NH2). The anabolic activities of RS-66271 and hPTHrP(1-34) were evaluated in 3-month-old, ovariectomized (OVX) osteopenic rats. Subcutaneous injection of hPTHrP(1-34) at 80 micrograms/kg/day partially reversed estrogen depletion trabecular bone loss but was ineffective in the cortex. In contrast, RS-66271 dose-relatedly reversed loss at both sites and, at 80 micrograms/kg/day, returned both trabecular and cortical bone calcium to the level of sham-operated controls. Histomorphometric analysis showed significantly elevated bone formation rates over vehicle-treated OVX in both trabecular and cortical tibial bone following treatment with RS-66271. Electron microscopy showed an increase in the relative surface area of vertebral trabeculae covered by osteoblasts in animals treated with RS-66271. These studies demonstrate that the C-terminal amino acids of hPTHrP(1-34) can be replaced by a model amphipathic helix and that the new chemical entity has greater anabolic activity than the parent peptide. The results suggest that RS-66271 may be a candidate molecule for the treatment of human osteoporosis.
Vickery
B H
BH
Inflammatory Disease Unit, Roche Bioscience, Palo Alvo, California, USA.
Avnur
Z
Z
Cheng
Y
Y
Chiou
S S
SS
Leaffer
D
D
Caulfield
J P
JP
Kimmel
D B
DB
Ho
T
T
Krstenansky
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000188:drug therapy*; D002118:Calcium / Q000378:metabolism; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000378:metabolism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D051381:Rats; D013131:Spine / Q000187:drug effects* / Q000378:metabolism; D019379:Teriparatide / Q000031:analogs & derivatives* / Q000494:pharmacology; D013977:Tibia / Q000187:drug effects* / Q000378:metabolism
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D019379:Teriparatide; C054296:parathyroid hormone-related protein (1-34); C104917:RS 66271; D002118:Calcium