Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys

Ominsky, Michael S.; Stouch, Brian; Schroeder, Joseph A.; Pyrah, Ian; Stolina, Marina; Smith, Susan Y.; Kostenuik, Paul J.

doi:10.1016/j.bone.2011.04.001

Cited by 96 publications

(85 citation statements)

References 43 publications

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“…This leads to the increased fragility of bone integrity and therefore an increased risk of bone fractures (27). The anti-RANKL antibody increases bone mineral density and decreases bone resorption in postmenopausal women and in ovariectomized monkeys (28,29), suggesting that an elevated RANKL ratio plays a role in bone loss in postmenopausal osteoporosis. RANKL induces the nuclear localization and phosphorylation of p65 in BMMs (6,30).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Iezaki

Fukasawa

Park

et al. 2016

Molecular and Cellular Biology

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Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor B (NF-B) ligand (RANKL) through activator protein 1. Global deletion of murine Ifrd1 increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion of Ifrd1 in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impaired in vitro in Ifrd1-deleted bone marrow macrophages (BMMs). Ifrd1 deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-B-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-B/NFATc1 axis plays a pivotal role in bone remodeling in vivo and represents a therapeutic target for bone diseases.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Iezaki

Fukasawa

Park

et al. 2016

Molecular and Cellular Biology

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“…Human RANKL (residues 143-317 of mRANKL) was produced in-house as a stable trimer of $61 kDa, as previously reported (Ominsky et al, 2011). Human OPG, residues 22-401 (OPG_D), was produced in-house as a stable dimer of $90 kDa MW, as previously reported (Lacey et al, 1998).…”

Section: Protein and Solution Systemsmentioning

confidence: 98%

Protein Assembly in Serum and the Differences from Assembly in Buffer

Hill

Laue

2015

Methods in Enzymology

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“…Inhibition of Signaling through the RANK receptor prevents osteoclast maturation, activation, and survival, thereby decreasing resorption of cortical and trabecular bone [15]. Inhibition of bone resorption with denosumab improves the structural strength of bone [16]. Treatment with denosumab has been associated with significant reductions in fracture risk across a wide range of patient groups [15,17].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Denosumab for the Treatment of Osteoporosis in Patients with Chronic Kidney Disease

Suzuki¹,

Kihara²,

Mano³

et al. 2017

J Clin Exp Nephrol

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Background: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and may lead to metabolic abnormalities that accelerate bone loss. Bisphosphonates, the most widely used treatment for osteoporosis, are contraindicated in patients with severe renal impairment. In the present study, we assessed whether denosumab is a safe and effective treatment for osteoporosis in patients with CKD.

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Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys

Cited by 96 publications

References 43 publications

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

Protein Assembly in Serum and the Differences from Assembly in Buffer

Efficacy and Safety of Denosumab for the Treatment of Osteoporosis in Patients with Chronic Kidney Disease

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