PTHrP(1-36) and Abaloparatide: Differential Regulators of Osteoblast Genes Compared with PTH(1-34)
Presentation Number: OR05-3
Date of Presentation: April 3rd, 2017
Florante Ricarte*1 and Nicola C Partridge2
1New York University School of Medicine, New York, NY, 2NYU, New York, NY
The intermittent administration of recombinant parathyroid hormone (PTH 1-34), or teriparatide, remains the only FDA-approved osteoanabolic therapy for the treatment of osteoporosis. However, prolonged use of teriparatide causes levels of bone resorption markers to rise to that of formation, thus limiting its usefulness. This “anabolic window” justifies the search for therapies that maximize anabolism, without incurring the resorptive effects of teriparatide. Miller et al. (2016) describe the phase III trial results of abaloparatide (ABL), a novel analog of parathyroid hormone-related protein (PTHrP 1-36), where similar anabolic effects are observed, but a lesser stimulation of resorption is induced with ABL compared with teriparatide or placebo (1). This study aims to elucidate the mechanisms that underlie the actions of PTHrP (1-36) and ABL in the osteoblast. Here, we show that in primary murine calvarial osteoblasts, administration of PTHrP (1-36) or ABL results in an attenuated cyclic AMP (cAMP) response compared to PTH (1-34). Time course and dose response curves revealed a maximal difference at 30 minutes and 1/2 max values of 9.3x10-9M and 2.52x10-8M for PTH (1-34) and PTHrP (1-36), respectively, whereas cAMP stimulation was nearly undetectable upon treatment with ABL, even at 10-6M. Consequently, the activation of protein kinase A (PKA) upon PTHrP (1-36) or ABL administration was also attenuated and this difference was maximally observed as soon as 60 sec. post-treatment. These events resulted in the differential sub-cellular localization of the transcriptional repressor, histone deacetylase 4 (HDAC4), where PTH (1-34) led to its nuclear export, while PTHrP (1-36) and ABL did not. Lastly, real-time quantitative PCR revealed differential expression of key osteoblastic genes, receptor activator of nuclear factor kappa-B ligand (RANKL) and transcription factor, c-fos, where PTH (1-34) treatment resulted in increased RANKL expression 3-fold greater and c-fos expression 2-fold greater compared with PTHrP (1-36) and ABL (n=3, p<0.05). These data suggest that PTH (1-34) utilizes the cAMP/PKA arm of this pathway at a much greater degree compared with PTHrP (1-36) and ABL and that the latter two peptides may employ alternative modes of signaling. Taken together, this study may provide a possible explanation for the effects of PTHrP (1-36) and ABL with respect to bone remodeling and illuminate a potentially novel therapy in the treatment of osteoporosis.
Nothing to Disclose: FR, NCP