Recent findings demonstrate that PTHrP, the other ligand of the PTH/PTHrP receptor (PTHR1), also decreased potently Sost mRNA expression in osteocyte-containing cultures of murine calvaria cells. To determine whether activation of the PTHR1 in osteocytes is sufficient for Sost inhibition, we generated transgenic mice expressing a constitutively active PTHR1 specifically in osteocytes. The transgene consisted of the DNA sequence of one of the constitutively active receptors described in Jansen's metaphyseal chondrodysplasia (H223R mutant) 12, 13 driven by the 8 kB portion of the promoter of the dentin matrix protein 1 (DMP1) gene. This promoter was previously shown to direct osteocyte specific expression of genes in transgenic mice. DMP1-caPTH1R transgenic mice express significantly reduced levels of Sost mRNA in vertebral and tibial bone as compared to wild type littermates at 10 weeks of age. Reduced Sost mRNA expression in vertebral bone lysates was also found in transgenic mice expressing the caPTH1R in both osteoblasts and osteocytes under the control of the 2.3 kb-collagen 1 promoter (2.3 col-caPTH1R mice) 13. On the other hand, the expression of Axin 2 and SMAD 6–Wnt and BMP target genes, respectively–and the osteoblast specific genes osteocalcin and collagen1a1 was elevated DMP1-caPTH1R mice. Strikingly, DMP1-caPTHR1 mice exhibit a remarkable increase in BMD, as measured by Dexa (Piximus) and micro-CT, and strength in both the axial and appendicular skeleton. We conclude that PTHR1 signaling in osteocytes is sufficient for inhibition of Sost expression and leads to a concomitant increase in bone mass. These findings are consistent with a direct action of PTH on osteocytes and suggest that the increased osteoblast number induced by PTH or PTHrP results, in part, from decreased Sost expression in osteocytes.