The Optimal Duration of PTH(1–34) Infusion Is One Hour per Day to Increase Bone Mass in Rats

Shimizu, Masaru; Noda, Hiroshi; Joyashiki, Eri; Nakagawa, Chihiro; Asanuma, Kentaro; Hayasaka, Akira; Kato, Motohiro; Nanami, Masahiko; Inada, Masaki; Miyaura, Chisato; Tamura, Tatsuya

doi:10.1248/bpb.b15-00756

Cited by 16 publications

(15 citation statements)

References 23 publications

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“…In our study, we found that 18β-GA had little effect on osteoclast precursor proliferation, significantly inhibited RANK expression which subsequently induces differentiation of osteoclast precursors into osteoclasts. After RANKL binding to RANK on preosteoclasts, TRAFs were recruited, which led to the activation of the NF-κB and MAPK pathways ( Shimizu et al, 2016 ; Zeng et al, 2017 ). Treatment with 18β-GA inhibited RANKL-mediated phosphorylation of p65, p50, and IκB in the NF-κB pathway and ERK, JNK and p38 in the MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

18β-Glycyrrhetinic Acid Inhibits Osteoclastogenesis In Vivo and In Vitro by Blocking RANKL-Mediated RANK–TRAF6 Interactions and NF-κB and MAPK Signaling Pathways

et al. 2018

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Bone metabolism is determined by a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. The imbalance due to over-activated osteoclasts plays an important role in various diseases. Activation of NF-κB and MAPK signaling pathways by receptor activator of nuclear factor -κB ligand (RANKL) is vital for osteoclastogenesis. Here, we for the first time explored the effects of 18β-glycyrrhetinic acid (18β-GA), a pentacyclic triterpenoid found in the Glycyrrhiza glabra L roots, on RANKL-induced osteoclastogenesis, osteoclast functions and signaling pathways in vitro and in vivo. In bone marrow monocytes (BMMs) and RAW264.7 cells, 18β-GA inhibited osteoclastogenesis, decreased expression of TRAP, cathepsin K, CTR and MMP-9, blocked actin ring formation and compromised osteoclasts functions in a dose-dependent manner at an early stage with minimal effects on osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). For underlying molecular mechanisms, 18β-GA inhibited RANKL-induced phosphorylation of p65, p50, and IκB, blocked p65 nuclear translocation and decreased the DNA-binding activity of NF-κB. Besides, 18β-GA inhibited the activation of the MAPK pathways. Co-immunoprecipitation showed that 18β-GA treatment blocked RANK–TRAF6 association at an upstream site. In vivo, 18β-GA treatment inhibited ovariectomy-induced osteoclastogenesis and reduced bone loss in mice. Overall, our results demonstrated that 18β-GA inhibited RANKL-induced osteoclastogenesis by inhibiting RANK expression in preosteoclasts and blocking the binding of RANK and TRAF6 which lead to the inhibition of NF-κB and MAPK signaling pathways. 18β-GA is a promising novel candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis.

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Section: Discussionmentioning

confidence: 99%

18β-Glycyrrhetinic Acid Inhibits Osteoclastogenesis In Vivo and In Vitro by Blocking RANKL-Mediated RANK–TRAF6 Interactions and NF-κB and MAPK Signaling Pathways

et al. 2018

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“…Osteocytes express type-1 PTH/PTHrP receptors (PTH1Rs), which are fully activated by aminoterminal PTH fragments and couple to multiple signal transducers, including adenylyl cyclase and phospholipase C. Intermittent administration of PTH is known to enhance bone mass, while continuous infusion of PTH decreases bone mineral density by increasing bone resorption [26]. Therefore, the regulation of PTH is a very delicate process that depends on the dose and frequency.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone (PTH) Induces Autophagy to Protect Osteocyte Cell Survival from Dexamethasone Damage

et al. 2017

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BackgroundGlucocorticoids (GC) have direct adverse effects on osteocytes, the most abundant bone cell type, and play an important role in osteonecrosis of the femoral head (ONFH). Teriparatide has been reported to be an effective treatment for ONFH. However, the underlying mechanism is unclear.Material/MethodsAn osteocyte cell line, MLO-Y4, was used under various doses of dexamethasone (Dex) with or without rhPTH (1–34). Cell viability, autophagy, and apoptosis markers and osteocyte characteristic mRNAs were investigated to better understand this phenomenon.ResultsInduction of apoptosis by Dex was increased in a time- and dose-dependent manner in MLO-Y4 cells. Autophagy markers (LC3-II and Beclin-1) were increased at the low dose of Dex (10−7 or 10−6 M) and decreased at the high dose (10−5 M). In MOL-Y4 cells, rhPTH (1–34) was shown to be protective against Dex-induced apoptosis. The upregulation of LC3-II and Beclin-1 and decreased level of Caspase-3 was observed in the rhPTH (1–34)-treated group compared with the Dex-only-treated group. Furthermore, the changes induced by Dex in osteocytes, such as increased SOST, RANKL, and DMP-1 mRNA level and decreased Destrin mRNA level, were reversed by rhPTH (1–34). A similar result was found in osteocyte-specific proteins sclerostin expression encoded by SOST mRNA, which acted as a bone formation inhibitor.ConclusionsThe self-activation of autophagy may be a protective mechanism against apoptosis induced by Dex. The protection effect of rhPTH (1–34) for GC-induced ONFH thus results, at least in part, from enhanced autophagy.

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“…Continuous secretion of PTH is associated with increased bone turnover in favor of bone resorption through upregulation of RANKL and downregulation of OPG [ 37 , 38 ]. However, when given intermittently to patients for a short period of time, PTH increases bone turnover in favor of bone formation and is currently used as a treatment for osteoporosis [ 38 , 39 ]. The mechanisms by which PTH regulates RANKL and OPG production in the bone are not completely understood, but the Wnt/ β -catenin pathway is likely to be involved.…”

Section: Overview Of Wnt/ β -Catenin Pathwaymentioning

confidence: 99%

Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy

Bisson

Ung

2018

International Journal of Endocrinology

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Vascular calcification and bone fragility are common and interrelated health problems that affect chronic kidney disease (CKD) patients. Bone fragility, which leads to higher risk of fracture and mortality, arises from the abnormal bone remodeling and mineralization that are seen in chronic kidney disease. Recently, sclerostin and Dickkopf-related protein 1 were suggested to play a significant role in CKD-related bone disease as they are known inhibitors of the Wnt pathway, thus preventing bone formation. This review focuses on new knowledge about the Wnt pathway in bone, how its function is affected by chronic kidney disease and how this affects bone structure. Expression of components and inhibitors of the Wnt pathway has been shown to be affected by the loss of kidney function, and a better understanding of the bone effects of Wnt pathway inhibitors could allow the development of new therapies to prevent bone fragility in this population.

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The Optimal Duration of PTH(1–34) Infusion Is One Hour per Day to Increase Bone Mass in Rats

Cited by 16 publications

References 23 publications

18β-Glycyrrhetinic Acid Inhibits Osteoclastogenesis In Vivo and In Vitro by Blocking RANKL-Mediated RANK–TRAF6 Interactions and NF-κB and MAPK Signaling Pathways

18β-Glycyrrhetinic Acid Inhibits Osteoclastogenesis In Vivo and In Vitro by Blocking RANKL-Mediated RANK–TRAF6 Interactions and NF-κB and MAPK Signaling Pathways

Parathyroid Hormone (PTH) Induces Autophagy to Protect Osteocyte Cell Survival from Dexamethasone Damage

Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy

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