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Enhanced Skeletal Anabolism by Concurrently Targeting the Parathyroid Hormone 1 Receptor (PTH1R) and Extracellular Calcium-Sensing Receptor (CaSR)

  • Author(s): Santa Maria, Christian Norman Davey Yuzon
  • Advisor(s): Den Besten, Pamela
  • et al.
Abstract

Maintaining normal Ca2+ homeostasis is essential for all biological functions. Parathyroid glands (PTGs) were developed in land vertebrates to defend against hypocalcemic challenges by tightly regulated secretion of parathyroid hormone (PTH), which activates the PTH1R in target tissues to increase Ca2+ recycling in kidneys, Ca2+ absorption from the small intestine via indirect renal production of 1,25-dihydroxyvitamin D3 (1,25-D), and Ca2+ release from bone matrices. These PTH-mediated calciotropic activities are subsided by elevated concentrations of serum Ca2+ through actions of its putative receptor, the extracellular Ca2+-sensing receptor (CaSR), in PTGs to suppress PTH secretion, in kidneys to enhance Ca secretion, and in bone to remineralize matrices and suppress bone resorbing activity, together with PTH/ PTH1R, constituting a “yin/yang” feedback mechanism to maintain Ca2+ homeostasis at a steady state. Interestingly, intermittent PTH (iPTH), administered by once-daily injections, can produce skeletal anabolism in the presence of Ca2+ sufficiency. However, more effective dosages could not be achieved for clinical use, mainly due to its intolerable hypercalcemic side-effects. This dissertation explores interplays between the actions of PTH1R and CaSR and exploits these interactions to harness hypercalcemic effects of PTH while enhancing its skeletal anabolism to prevent bone loss and enhance bone fracture repair. Our strategy leverages the ability of co-injecting an allosteric agonist of CaSR (or calcimimetic) to normalize PTH induced hypercalcemia and synergize anabolic actions of CaSR and PTH1R in bone cells. The study employed state-of-the-art technologies, including high-resolution microCT imaging, automated comprehensive serological assays, Nanostring nCounter gene expression profiling, steady and dynamic histomorphometry, biomechanics testing, and novel genetically manipulated murine models. Our findings reveal novel synergistic actions of PTH and CaSR in bone and their underlying mechanisms, which hold powerful clinical implications for future strategies needed to treat osteoporotic disease and skeletal fractures.

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