Increased PHOSPHO1 and alkaline phosphatase expression during the anabolic bone response to intermittent parathyroid hormone delivery

Abstract

The administration of intermittent parathyroid hormone (iPTH) is anabolic to the skeleton. Recent studies with cultured osteoblasts have revealed that the expression of PHOSPHO1, a bone-specific phosphatase essential for the initiation of mineralisation, is regulated by PTH. Therefore, this study sought to determine whether the bone anabolic response to iPTH involves modulation of expression of Phospho1 and of other enzymes critical for bone matrix mineralisation. To mimic iPTH treatment, primary murine osteoblasts were challenged with 50 nM PTH for 6 h in every 48 h period for 8 days (4 cycles), 14 days (7 cycles) and 20 days (10 cycles) in total. The expression of both Phospho1 and Smpd3 was almost completely inhibited after 4 cycles, whereas 10 cycles were required to stimulate a similar response in Alpl expression. To explore the in vivo role of PHOSPHO1 in PTH-mediated osteogenesis, the effects of 14-and 28-day iPTH (80 μg/kg/day) administration was assessed in male wild-type (WT) and Phospho1 −/− mice. The expression of Phospho1, Alpl, Smpd3, Enpp1, Runx2 and Trps1 expression was enhanced in the femora of WT mice following iPTH administration but remained unchanged in the femora of Phospho1 −/− mice. After 28 days of iPTH administration, the anabolic response in the femora of WT was greater than that noted in Phospho1 −/− mice. Specifically, cortical and trabecular bone volume/total volume, as well as cortical thickness, were increased in femora of iPTH-treated WT but not in iPTH-treated Phospho1 −/− mice. Trabecular bone osteoblast number was also increased in iPTH-treated WT mice but not in iPTH-treated Phospho1 −/− mice. The increased levels of Phospho1, Alpl, Enpp1 and Smpd3 in WT mice in response to iPTH administration is consistent with their contribution to the potent anabolic properties of iPTH in bone. Furthermore, as the anabolic response to iPTH was attenuated in

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

“…Furthermore, PTH can initiate the conversion of lining cells into osteoblasts and slow down the progression of osteoblasts back into lining cells [ 2 , 105 , 106 ]. The processes that promote osteogenesis are multifaceted, including the activation of osteoprogenitor cells or osteoblasts and the initiation of mineralization [ 107 ]. This leads to the enhanced activity of osteoblasts, reduced death of these bone-forming cells, heightened PKA/PKC signaling, Wnt/β-catenin signaling, MAPK signaling, and adjustment of the RANKL/OPG pathway, all contributing to the upsurge in bone formation [ 108 ] ( Figure 2 ).…”