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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 intra-cortical remodeling and cortical porosity. Crossing DMP1-caPTHR1 mice with
mice lacking the Wnt co-receptor LDL 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.
Key words: osteocytes, PTH receptor, periosteal bone formation, Wnt signaling, intracortical
remodeling