Parathyroid hormone (PTH) and PTH-related
protein (
PTHrP) are believed to exert their
biological actions through binding and activation of a common
cell surface receptor. Recently, an analog of
PTHrP (RS-66271), was described that demonstrated reduced binding affinity for the
PTH/PTHrP receptor compared with bovine
PTH(1-34) but retained equal
biological activity. The present study investigated the receptor binding affinities of synthetic
RS-66271 and recombinant human
PTH(1-34) (LY333334) and compared their in vitro and in vivo pharmacological effects.
RS-66271 had one hundredth the activity of
PTH(1-34) in competing for the binding of [125I] [Nle8,18, Tyr34]human
PTH(1-34) to the human
PTH/PTHrP receptor stably expressed in a human kidney cell line. Despite this reduced binding affinity,
RS-66271 had equivalent activity in increasing both cAMP production in osteoblast-like cells and
bone resorption in neonatal mouse calvariae. However,
RS-66271 was 7. 6-fold less active in stimulating
inositol phosphate production. For in vivo studies, young, male Fisher rats received a daily subcutaneous dose of either 10 or 40 microg/kg of
peptide for 1, 2, or 4 weeks. Volumetric bone mineral density and total bone mineral content of the proximal tibia were determined by peripheral quantitative computerized tomography. Trabecular and cortical bone of the distal femur were analyzed for
calcium and dry weight. Lumbar vertebrae (L4-L6) were analyzed by histomorphometry. Trabecular and cortical bone mass showed a dose- and time-dependent increase in the treated animals compared with the controls. These increases were evident as early as 1 week after initiation of dosing. There were no consistent significant differences in the comparative effects of
PTH(1-34) and
RS-66271 on the measured bone parameters. In conclusion, despite the reduced binding affinity of
RS-66271 for the
PTH/PTHrP receptor compared with human
PTH(1-34), both
peptides displayed similar in vitro and in vivo pharmacological effects.