β-Arrestin2 Regulates RANKL and Ephrins Gene Expression in Response to Bone Remodeling in Mice

Pierroz, Dominique D.; Rufo, Anna; Bianchi, Estelle N.; Glatt, Vaida; Capulli, Mattia; Rucci, Nadia; Cavat, Fanny; Rizzoli, René; Teti, Anna; Bouxsein, Mary L.; Ferrari, Serge

doi:10.1359/jbmr.081237

Cited by 37 publications

(30 citation statements)

References 42 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, numerous factors have been described that can either stimulate or inhibit osteoblast maturation such as BMPs and the Ephrin/Eph bidirectional signaling between osteoblast and osteoclast (44)(45)(46)(47)(48)(49). The results of this study indicate that inhibiting RANKL signaling in GCTB induces bone formation by tumor stromal cells either indirectly by eliminating factors associated with tumor giant cells or by direct action on the tumor stromal cell to form bone.…”

Section: Discussionmentioning

confidence: 67%

Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

Branstetter

Nelson

Manivel

et al. 2012

Clinical Cancer Research

369

301

View full text Add to dashboard Cite

Purpose: Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB.Experimental Design: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a 90% or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL.Results: Baseline tumor samples were typically composed of densely cellular proliferative RANKLpositive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells.Conclusions: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANKpositive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.

show abstract

Section: Discussionmentioning

confidence: 67%

Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

Branstetter

Nelson

Manivel

et al. 2012

Clinical Cancer Research

369

301

View full text Add to dashboard Cite

show abstract

“…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.

129

112

View full text Add to dashboard Cite

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.

show abstract

“…Osteoid surface and osteocalcin mRNA levels are increased, consistent with an increase in the rate of bone formation. At the same time bone, resorption is accelerated, as evidenced by increased osteoclast surface, marrow osteoclast precursors, and bone turnover markers, such as receptor activator of NFB ligand and osteoprotegerin mRNA and urine deoxypyridinoline (Gesty-Palmer et al, 2009;Pierroz et al, 2009). Arrestin3-null mice have an impaired anabolic response to exogenous PTH(1-34), with blunted increases in bone volume and trabecular thickness and no change in trabecular number, periosteal circumference, or cortical thickness compared with control mice.…”

Section: E Skeletal Remodelingmentioning

confidence: 99%

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

2010

View full text Add to dashboard Cite

β-Arrestin2 Regulates RANKL and Ephrins Gene Expression in Response to Bone Remodeling in Mice

Cited by 37 publications

References 42 publications

Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

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

Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling

Contact Info

Product

Resources

About