PTH Receptor Signaling in Osteocytes Governs Periosteal Bone Formation and Intracortical Remodeling

YUMIE RHEE; MATTHEW R ALLEN; KEITH CONDON; VIRGINIA LEZCANO; ANA C RONDA; CARLO GALLI; NAOMI OLIVOS; GIOVANNI PASSERI; CHARLES A OBRIEN; NICOLETTA BIVI; LILIAN I PLOTKIN; TERESITA BELLIDO

JOURNAL OF BONE AND MINERAL RESEARCH

AMER SOC BONE & MINERAL RES

Año: 2011 vol. 26 p. 1035 - 1046

0884-0431

The periosteal and endocortical surfaces of cortical bone dictate the geometry and overall mechanical properties of bone. Yet, the cellular and molecular mechanisms that regulate activity on these surfaces are far from being understood. Parathyroid hormone (PTH) has profound effects in cortical bone, stimulating periosteal expansion and at the same time accelerating intra-cortical bone remodeling. We report herein that transgenic mice expressing a constitutive active PTH receptor in osteocytes (DMP1-caPTHR1 mice) exhibit increased cortical bone area and elevated rate of periosteal and endocortical bone formation. In addition, DMP1-caPTHR1 mice display marked increase in intracortical remodeling and cortical porosity. Crossing DMP1-caPTHR1 mice with mice lacking the Wnt coreceptor related receptor 5 (LRP5) or with mice overexpressing the Wnt antagonist Sost in osteocytes (DMP1-Sost mice), reduced or completely abolished, respectively, the increased cortical bone area, periosteal BFR, and expression of osteoblast markers and Wnt target genes exhibited by the DMP1-caPTHR1 mice. In addition, DMP1-caPTHR1 lacking LRP5 or double transgenic DMP1-caPTHR1;DMP1-Sost mice exhibit exacerbated intra-cortical remodeling and osteoclast numbers, and markedly decreased expression of the RANK decoy receptor osteoprotegerin (OPG). Thus, whereas Sost downregulation and the consequent Wnt activation is required for the stimulatory effect of PTH receptor signaling on periosteal bone formation, the Wnt-independent increase in osteoclastogenesis induced by PTH receptor activation in osteocytes overrides the effect on Sost. These findings demonstrate that PTH receptor signaling influences cortical bone through actions on osteocytes and define the role of Wnt signaling in PTH receptor action.