Contributions of parathyroid hormone (PTH)/PTH-related peptide receptor signaling pathways to the anabolic effect of PTH on bone

Abstract

PTH regulates osteoblastic function by activating PTH/PTHrP receptors (PTH1Rs), which trigger several signaling pathways in parallel, including cAMP/protein kinase A (PKA) and, via both phospholipase-C (PLC)-dependent and PLC-independent mechanisms, protein kinase C (PKC). These signaling functions have been mapped to distinct domains within PTH(1-34), but their roles in mediating the anabolic effect of intermittent PTH in vivo are unclear. We compared the anabolic effects in mice of hPTH(1-34) with those of two analogs having restricted patterns of PTH1R signaling. [G 1 ,R 19 ]hPTH(1-28) lacks the 29-34 domain of hPTH(1-34) needed for PLCindependent PKC activation, incorporates a Gly 1 mutation that prevents PLC activation, and stimulates only cAMP/PKA signaling. [G 1 ,R 19 ]hPTH(1-34) retains the 29-34 domain and activates both cAMP/PKA and PLC-independent PKC.Human PTH(1-34) (40 μg/kg), [G 1 ,R 19 ]hPTH(1-34) (120 μg/kg), and [G 1 ,R 19 ]hPTH(1-28) (800 μg/kg), at doses equipotent in elevating blood cAMP at 10 min and cAMP-dependent gene expression in bone at 6 h after s.c. injection, were administered to 10 week old female C57BL/6J mice 5 days/ week for 4 weeks. Acute blood cAMP responses, retested after 4 weeks, were not reduced by the preceding PTH treatment. The three PTH peptides induced equivalent increases in distal femoral bone mineral density (BMD), and, by microCT analysis, distal femoral and vertebral bone volume and trabecular thickness and mid-femoral cortical endosteal apposition. [G 1 ,R 19 ]hPTH(1-34) and hPTH(1-34) increased distal femoral BMD more rapidly and augmented total-body BMD and bone volume of proximal tibial trabeculi to a greater extent than did [G 1 ,R 19 ]hPTH(1-28),.We conclude that cAMP/PKA signaling is the dominant mechanism for the anabolic actions of PTH in trabecular bone and PLC-independent PKC signaling, attributable to the PTH(29-34) sequence, appears to accelerate the trabecular response and augment BMD at some skeletal sites. PTH1R PLC signaling pathway is not required for an anabolic effect of intermittent PTH(1-34) on bone.

International Union of Basic and Clinical Pharmacology. XCIII. The Parathyroid Hormone Receptors—Family B G Protein–Coupled Receptors

“…Whether this reflects a more efficient coupling of the PTHR1 to Ga s than to Ga q (Iida-Klein et al, 1997), a difference in the pharmacophoric determinants in the ligand and receptor that mediate activation of the two pathways, the more amplified nature of the cellular cAMP response, or a combination of such factors is unclear. The experimental results nevertheless tend to support the notion that although the PLC/IP 3 /PKC and potentially other pathways may help regulate responses induced by PTH and PTHrP ligands in bone and kidney target cells, it is the cAMP/PKA pathway that plays the dominant role in mediating the biologic actions of these ligands in vivo (Guo et al, 2002(Guo et al, , 2010Yang et al, 2007).…”

Serum Amyloid A3 Secreted by Preosteoclasts Inhibits Parathyroid Hormone-stimulated cAMP Signaling in Murine Osteoblasts

“…There was no inhibitory effect on PTH-stimulated osteoblastic differentiation if the CM came from Cox2 KO BMMs. Many studies suggest that PTH mediates its osteogenic effects in vitro or its anabolic effects in vivo largely via G␣ s -cAMP-dependent protein kinase A (PKA) signaling (2,16,17). Therefore, we examined the effect of inhibitory CM on PTH-stimulated cAMP signaling in POBs.…”

“…Parathyroid hormone (PTH) 2 acts on a G protein-coupled receptor (GPCR), PTH1R, to regulate calcium homeostasis and bone remodeling, stimulating both bone resorption and formation (1). PTH stimulates bone formation primarily by activating a G␣ s -dependent cAMP/protein kinase A (PKA) signaling pathway (2).…”

“…PTH stimulates bone formation primarily by activating a G␣ s -dependent cAMP/protein kinase A (PKA) signaling pathway (2). PTH stimulates bone resorption by acting on osteoblastic lineage cells to increase the expression of RANKL and decrease the expression of osteoprotegerin (OPG), a decoy receptor for RANKL (3).…”

Bioluminescence imaging in bone tissue engineering

“…Parathyroid hormone (PTH) has an anabolic effect on bone formation by stimulating proliferation and differentiation of osteoblast precursors and promoting the synthetic activities of mature osteoblasts [119]. The positive effect of PTH on differentiation is supposed to be mediated by the PKA signaling pathway while its effect on proliferation is thought to be mediated by PKC [120,121]. A role of PKC in cellular proliferation has been delineated in a number of osteogenic cell types.…”