Abstract
PTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene Lrp6, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to intermittent PTH (iPTH) treatment. We hypothesized that maintaining enough functional PTH1R/LRP6 coreceptor complexes at the plasma membrane through NACA-dependent Lrp6 transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of Naca and Lrp6 is inactivated in osteoblasts and osteocytes, using a knock-in strain with a Naca99 Ser-to-Ala mutation and an Lrp6 floxed strain (test genotype: Naca99S/A; Lrp6+/fl;OCN-Cre). Four-month-old females were injected with vehicle or 100 μg/kg PTH(1-34) once daily, 5 days a week for 4 weeks. Control mice showed significant increases in vertebral trabecular bone mass and biomechanical properties that were abolished in compound heterozygotes. Lrp6 expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased Alpl and Col1a1 mRNA levels in the control but not in the test group. These results confirm that NACA and LRP6 form part of a common genetic pathway that is necessary for the full anabolic effect of iPTH.
Highlights
Administering PTH at a low dosage once a day promotes bone formation through pleiotropic effects on osteoblasts and osteocytes [1,2,3]
Our results show that the PTH-PKA-NACA pathway is necessary for the full anabolic effect of intermittent PTH (iPTH) and that Naca and Lrp6 are part of a common genetic pathway regulating bone mass downstream of iPTH treatment
These resultsofshow that phosphorylation residue 99Smutant is essential mediate. These results show that phosphorylation of residue is essential to mediate the full in the response to iPTH treatment and confirm the physiological role played by NACA
Summary
Administering PTH at a low dosage once a day (intermittent PTH; iPTH) promotes bone formation through pleiotropic effects on osteoblasts and osteocytes [1,2,3]. Upon PTH binding to its receptor (PTH1R), Gαs is activated to stimulate cAMP accumulation and PKA activity, resulting in phosphorylation of NACA, a protein shuttling between the cytoplasm and the nucleus. Phosphorylation of NACA on residue Serine 99 (99S) by PKA sends it to the nucleus [6], where it assembles with transcription factors such as JUN or JUND homodimers and components of the general transcriptional machinery to activate transcription of the osteocalcin (Bglap2) and Lrp Protein 6) genes [7,8,9,10] This function of NACA as a transcriptional coregulator of osteogenic target genes is physiologically relevant to control bone mass [6,8]
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