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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 <i>Lrp6</i>, 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 <i>Lrp6</i> transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of <i>Naca</i> and <i>Lrp6</i> is inactivated in osteoblasts and osteocytes, using a knock-in strain with a <i>Naca</i>⁹⁹ Ser-to-Ala mutation and an <i>Lrp6</i> floxed strain (test genotype: <i>Naca</i>^99S/A; <i>Lrp6</i>^+/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. <i>Lrp6</i> expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased <i>Alpl</i> and <i>Col1a1</i> 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.