Comparison of recombinant human PTH(1-34) (LY333334) with a C-terminally substituted analog of human PTH-Related protein (1-34) (RS-66271): In vitro activity and in vivo pharmacological effects in rats

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are believed to e xert their biological actions through binding and activation of a common ce ll surface receptor, Recently, an analog of PTHrP (RS-66271), was described that demonstrated reduced binding affinity for the PTH/PTHrP receptor comp ared with bovine PTH(1-34) but retained equal biological activity. The pres ent study investigated the receptor binding affinities of synthetic RS-6627 1 and recombinant human PTH(1-34) (LY333334) and compared their in vitro an d in vivo pharmacological effects, RS-66271 had one hundredth the activity of PTH(1-34) in competing for the binding of [I-125][Nle(8,18) Tyr(34)]huma n PTH(1-34) to the human PTH/PTHrP receptor stably expressed in a human kid ney cell line. Despite this: reduced binding affinity, RS-66271 had equival ent activity in increasing both cAMP production in osteoblastlike cells and bone resorption in neonatal mouse calvariae, However, RS-66271 was 7.6-fol d less active in stimulating inositol phosphate production. For in vivo stu dies, young, male Fisher rats received a daily subcutaneous dose of either 10 or 40 mu g/kg of peptide for 1, 2, or 4 weeks, Volumetric bone mineral d ensity and total bone mineral content of the proximal tibia were determined by peripheral quantitative computerized tomography, Trabecular and cortica l bone of the distal femur were analyzed for calcium and dry weight, Lumbar vertebrae (A4-L6) were analyzed by histomorphometry, Trabecular and cortic al bone mass showed a dose- and time-dependent increase in the treated anim als compared with the controls, These increases were evident as early as 1 week after initiation of dosing. There were no consistent significant diffe rences 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 pept ides displayed similar in vitro and in vivo pharmacological effects.