β-Arrestin2 Regulates the Differential Response of Cortical and Trabecular Bone to Intermittent PTH in Female Mice

Bouxsein, Mary L.; Pierroz, Dominique D.; Glatt, Vaida; Goddard, Deborah S.; Cavat, Fanny; Rizzoli, R.; Ferrari, Serge

doi:10.1359/jbmr.041204

Cited by 72 publications

(70 citation statements)

References 58 publications

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“…At clinically relevant doses, indeed (i.e., less than 40 μg·kg·d in mice and 20 μg/d in humans), PTH exerts relatively modest (if any) bone anabolic effects on the periosteum, contrasting with its strong endocortical anabolism (34)(35)(36). The latter is largely explained by the fact that activation of osteoblast lining cells is potentiated by key growth factors and clastokines normally released at bone resorbing surfaces.…”

Section: Discussionmentioning

confidence: 99%

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Bonnet

Conway

Ferrari

2012

Proc. Natl. Acad. Sci. U.S.A.

130

112

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Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn −/− and Postn +/+ mice to intermittent PTH. Compared with Postn +/+ , Postn −/− mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn −/− mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn −/− mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn −/− mice. In addition, primary osteoblasts from Postn −/− mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn −/− osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Bonnet

Conway

Ferrari

2012

Proc. Natl. Acad. Sci. U.S.A.

130

112

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“…We assessed trabecular and cortical bone architecture at week 8 using micro-CT (CT40, Scanco Medical AG, Basserdorf, Switzerland), employing a 12 m isotropic voxel size. Specifically, trabecular bone architecture as well as cortical width (as the mean of the whole section) were evaluated at the 5th lumbar vertebra and distal femoral metaphysis, whereas cortical bone morphology was evaluated at the femoral mid-shaft, as previously described (33,34).…”

Section: Methodsmentioning

confidence: 99%

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

Pierroz

Bonnet

Baldock

et al. 2010

Journal of Biological Chemistry

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PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover, -i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK ؊/؊ mice. PTH increased osteocalcin similarly in RANK ؊/؊ and WT mice. It also increased BMD in RANK ؊/؊ mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.Parathyroid hormone (PTH), 2 when administered intermittently, increases bone mineral density (BMD) and improves bone microarchitecture and strength (1). PTH induces a rapid increase in markers of bone formation before it also increases bone resorption, which has been described as an "anabolic window" (2). In this window, PTH has been suggested to directly activate bone formation via bone lining cells on quiescent bone surfaces (i.e. modeling surfaces), as indicated by an increase in double tetracycline-labeled surfaces and a smooth cement line (3). PTH subsequently stimulates bone remodeling, first through activation of osteoclastic bone resorption in the basic multicellullar units (BMU), followed by new bone formation by osteoblasts. These remodeling-based BMUs are associated with scalloped cement lines by microscopy. Data from untreated adult rodents indicate that the ratio of bone modeling:remodeling surfaces is less than 1:5 and further decreases with age (4). Although PTH has been shown to increase bone modeling in rodents, the vast majority of bone formation in humans appears to be remodeling-based (5). Data from humans treated with PTH indicate that bone formation on modeling surfaces accounts for only 5-30% of PTH anabolic effects (6). While intermittent PTH can partially restore bone microarchitecture by increasing bone formation in mo...

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“…Quantitative microcomputed tomography (μCT40, Scanco Medical AG, Basserdorf, Switzerland) was used ex vivo to assess three-dimensional (3D) trabecular bone morphology in the 5 th lumbar vertebrae and distal femoral metaphysis and cortical bone geometry at the mid-femoral diaphysis using an 12 μm isotropic voxel size [2,3]. Morphometric variables were computed from the binarized images using direct, three-dimensional techniques that do not rely on any prior assumptions about the underlying structure [8][9][10].…”

Section: μCt Analysismentioning

confidence: 99%

Contributions of parathyroid hormone (PTH)/PTH-related peptide receptor signaling pathways to the anabolic effect of PTH on bone

Yang

Singh

Divieti

et al. 2007

Bone

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PTH regulates osteoblastic function by activating PTH/PTHrP receptors (PTH1Rs), which trigger several signaling pathways in parallel, including cAMP/protein kinase A (PKA) and, via both phospholipase-C (PLC)-dependent and PLC-independent mechanisms, protein kinase C (PKC). These signaling functions have been mapped to distinct domains within PTH(1-34), but their roles in mediating the anabolic effect of intermittent PTH in vivo are unclear. We compared the anabolic effects in mice of hPTH(1-34) with those of two analogs having restricted patterns of PTH1R signaling. [G 1 ,R 19 ]hPTH(1-28) lacks the 29-34 domain of hPTH(1-34) needed for PLCindependent PKC activation, incorporates a Gly 1 mutation that prevents PLC activation, and stimulates only cAMP/PKA signaling. [G 1 ,R 19 ]hPTH(1-34) retains the 29-34 domain and activates both cAMP/PKA and PLC-independent PKC.Human PTH(1-34) (40 μg/kg), [G 1 ,R 19 ]hPTH(1-34) (120 μg/kg), and [G 1 ,R 19 ]hPTH(1-28) (800 μg/kg), at doses equipotent in elevating blood cAMP at 10 min and cAMP-dependent gene expression in bone at 6 h after s.c. injection, were administered to 10 week old female C57BL/6J mice 5 days/ week for 4 weeks. Acute blood cAMP responses, retested after 4 weeks, were not reduced by the preceding PTH treatment. The three PTH peptides induced equivalent increases in distal femoral bone mineral density (BMD), and, by microCT analysis, distal femoral and vertebral bone volume and trabecular thickness and mid-femoral cortical endosteal apposition. [G 1 ,R 19 ]hPTH(1-34) and hPTH(1-34) increased distal femoral BMD more rapidly and augmented total-body BMD and bone volume of proximal tibial trabeculi to a greater extent than did [G 1 ,R 19 ]hPTH(1-28),.We conclude that cAMP/PKA signaling is the dominant mechanism for the anabolic actions of PTH in trabecular bone and PLC-independent PKC signaling, attributable to the PTH(29-34) sequence, appears to accelerate the trabecular response and augment BMD at some skeletal sites. PTH1R PLC signaling pathway is not required for an anabolic effect of intermittent PTH(1-34) on bone.

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β-Arrestin2 Regulates the Differential Response of Cortical and Trabecular Bone to Intermittent PTH in Female Mice

Cited by 72 publications

References 58 publications

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

Are Osteoclasts Needed for the Bone Anabolic Response to Parathyroid Hormone?

Contributions of parathyroid hormone (PTH)/PTH-related peptide receptor signaling pathways to the anabolic effect of PTH on bone

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