Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2013

Open Access 01-12-2013 | Research article

Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells

Authors: Hiroki Yokota, Kazunori Hamamura, Andy Chen, Todd R Dodge, Nancy Tanjung, Aysan Abedinpoor, Ping Zhang

Published in: BMC Musculoskeletal Disorders | Issue 1/2013

Login to get access

Abstract

Background

Osteoporosis is a skeletal disease leading to an increased risk of bone fracture. Using a mouse osteoporosis model induced by administration of a receptor activator of nuclear factor kappa-B ligand (RANKL), salubrinal was recently reported as a potential therapeutic agent. To evaluate the role of salubrinal in cellular fates as well as migratory and adhesive functions of osteoclast/osteoblast precursors, we examined the development of primary bone marrow-derived cells in the presence and absence of salubrinal. We addressed a question: are salubrinal’s actions more potent to the cells isolated from the osteoporotic mice than those isolated from the control mice?

Methods

Using the RANKL-injected and control mice, bone marrow-derived cells were harvested. Osteoclastogenesis was induced by macrophage-colony stimulating factor and RANKL, while osteoblastogenesis was driven by dexamethasone, ascorbic acid, and β-glycerophosphate.

Results

The results revealed that salubrinal suppressed the numbers of colony forming-unit (CFU)-granulocyte/macrophages and CFU-macrophages, as well as formation of mature osteoclasts in a dosage-dependent manner. Salubrinal also suppressed migration and adhesion of pre-osteoclasts and increased the number of CFU-osteoblasts. Salubrinal was more effective in exerting its effects in the cells isolated from the RANKL-injected mice than the control. Consistent with cellular fates and functions, salubrinal reduced the expression of nuclear factor of activated T cells c1 (NFATc1) as well as tartrate-resistant acid phosphatase.

Conclusions

The results support the notion that salubrinal exhibits significant inhibition of osteoclastogenesis as well as stimulation of osteoblastogenesis in bone marrow-derived cells, and its efficacy is enhanced in the cells harvested from the osteoporotic bone samples.
Appendix
Available only for authorised users
Literature
1.
van den Bergh JP, van Geel TA, Geusens PP: Osteoporosis, frailty and fracture: implications for case finding and therapy. Nat Rev Rheumatol. 2012, 8: 163-172. 10.1038/nrrheum.2011.217.CrossRefPubMed
2.
Shiraki M, Kuroda T, Miyakawa N, Fujinawa N, Tanzawa K, Ishizuka A, Tanaka S, Tanaka Y, Hosoi T, Itoi E, Morimoto S, Itabashi A, Sugimoto T, Yamashita T, Gorai I, Mori S, Kishimoto H, Mizunuma H, Endo N, Nishizawa Y, Takaoka K, Ohashi Y, Ohta H, Fukunaga M, Nakamura T, Orimo H: Design of a pragmatic approach to evaluate the effectiveness of concurrent treatment for the prevention of osteoporotic fractures: rationale, aims and organization of a Japanese Osteoporosis Intervention Trial (JOINT) initiated by the Research Group of Adequate Treatment of Osteoporosis (A-TOP). J Bone Miner Metab. 2011, 29: 37-43. 10.1007/s00774-010-0188-x.CrossRefPubMed
3.
Vercini F, Grimaldi F: PTH 1–84: bone rebuilding as a target for the therapy of severe osteoporosis. Clin Cases Miner Bone Metab. 2012, 9: 31-36.
4.
Dempster DW, Lambing CL, Kostenuik PJ, Grauer A: Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data. Clin Ther. 2012, 34: 521-536. 10.1016/j.clinthera.2012.02.002.CrossRefPubMed
5.
Yang Q, Jian J, Abramson SB, Huang X: Inhibitory effects of iron on bone morphogenetic protein 2-induced osteoblastogenesis. J Bone Miner Res. 2011, 26: 1188-1196. 10.1002/jbmr.337.CrossRefPubMed
6.
Khosla S, Bilezikian JP, Dempster DW, Lewiecki EM, Miler PD, Neer RM, Recker RR, Shane E, Shoback D, Potts JT: Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab. 2012, 97: 2272-2282. 10.1210/jc.2012-1027.CrossRefPubMed
7.
Riggs BL, Khosla S, Melton LJ: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002, 23: 279-302. 10.1210/er.23.3.279.CrossRefPubMed
8.
Valverde P: Pharmacotherapies to manage bone loss-associated diseases: a quest for the perfect benefit-to-risk ratio. Curr Med Chem. 2008, 15: 284-304. 10.2174/092986708783497274.CrossRefPubMed
9.
Boras-Granic K, Wysolmerski JJ: PTHrP and breast cancer: more than hypercalcemia and bone metastases. Breast Cancer Res. 2012, 14: 307-10.1186/bcr3129.CrossRefPubMedPubMedCentral
10.
Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J: A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science. 2005, 307: 935-939. 10.1126/science.1101902.CrossRefPubMed
11.
Huang X, Chen Y, Zhang H, Ma Q, Zhang YW, Xu H: Salubrinal attenuates β-amyloid-induced neuronal death and microglial activation by inhibition of the NF-κB pathway. Neurobiol Aging. 2012, 33: 1007.e9-1007.e17. 10.1016/j.neurobiolaging.2011.10.007.CrossRef
12.
Saito A, Ochiai K, Kondo S, Tsumagari K, Murakami T, Cavener DR, Imaizumi K: Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem. 2011, 286: 4809-4818. 10.1074/jbc.M110.152900.CrossRefPubMed
13.
Zhang P, Hamamura K, Jiang C, Zhang L, Yokota H: Salubrinal promotes healing of surgical wounds in rat femurs. J Bone Miner Metab. 2012, 30: 568-579. 10.1007/s00774-012-0359-z.CrossRefPubMed
14.
Li X, Ling W, Khan S, Yaccoby S: Therapeutic effects of intrabone and systemic mesenchymal stem cell cytotherapy on myeloma bone disease and tumor growth. J Bone Miner Res. 2012, 27: 1635-1648. 10.1002/jbmr.1620.CrossRefPubMedPubMedCentral
15.
Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, Zaidi S, Zhu LL, Yaroslavskiy BB, Zhou H, Zallone A, Sairam MR, Kumar TR, Bo W, Braun J, Cardoso-Landa L, Schaffler MB, Moonga BS, Blair HC, Zaidi M: FSH directly regulates bone mass. Cell. 2006, 125: 247-260. 10.1016/j.cell.2006.01.051.CrossRefPubMed
16.
17.
Shahnazari M, Wronski T, Chu V, Williams A, Leeper A, Stolina M, Ke HZ, Halloran B: Early response of bone marrow osteoprogenitors to skeletal unloading and sclerostin antibody. Calcif Tissue Int. 2012, 91: 50-58. 10.1007/s00223-012-9610-9.CrossRefPubMed
18.
Zhang P, Hammamura K, Yokota H: A brief review of bone adaptation to unloading. Genomics Proteomics Bioinf. 2008, 6: 4-7. 10.1016/S1672-0229(08)60016-9.CrossRef
19.
Gaspar AP, Lazaretti-Castro M, Brandão CM: Bone mineral density in spinal cord injury: an evaluation of the distal femur. J Osteoporos. 2012, 2012: 519754-CrossRefPubMedPubMedCentral
20.
Jiang SD, Jiang LS, Dai LY: Mechanisms of osteoporosis in spinal cord injury. Clin Endocrinol (Oxf). 2006, 65: 555-565. 10.1111/j.1365-2265.2006.02683.x.CrossRef
21.
Omi N, Ezawa I: Animal models for bone and joint disease. Low calcium diet-induced rat model of osteoporosis. Clin Calcium. 2012, 21: 173-180.
22.
Chennaiah S, Vijayalakshmi V, Suresh C: Effect of the supplementation of dietary rich phytoestrogens in altering the vitamin D levels in diet induced osteoporotic rat model. J Steroid Biochem Mol Biol. 2010, 121: 268-272. 10.1016/j.jsbmb.2010.03.070.CrossRefPubMed
23.
Lo Iacono N, Blair HC, Poliani PL, Marrella V, Ficara F, Cassani B, Facchetti F, Fontana E, Guerrini MM, Traggiai E, Schena F, Paulis M, Mantero S, Inforzato A, Valaperta S, Pangrazio A, Crisafulli L, Maina V, Kostenuik P, Vezzoni P, Villa A, Sobacchi C: Osteopetrosis rescue upon RANKL administration to Rankl(−/−) mice: A new therapy for human RANKL-dependent ARO. J Bone Miner Res. 2012, 27: 2501-2510. 10.1002/jbmr.1712.CrossRefPubMed
24.
Campbell GM, Ominsky MS, Boyd SK: Bone quality is partially recovered after the discontinuation of RANKL administration in rats by increased bone mass on existing trabeculae: an in vivo micro-CT study. Osteoporosis Int. 2011, 22: 931-942. 10.1007/s00198-010-1283-5.CrossRef
25.
Yasuda H: Animal models for bone and joint disease. RANKL-injected bone loss model. Clin Calcium. 2011, 21: 197-208.PubMed
26.
Tomimori Y, Mori K, Koide M, Nakamichi Y, Ninomiya T, Udagawa N, Yasuda H: Evaluation of pharmaceuticals with a novel 50-hour animal model of bone loss. J Bone Miner Res. 2009, 24: 1194-1205. 10.1359/jbmr.090217.CrossRefPubMed
27.
Wasilewska A, Rybi-Szuminska AA, Zoch-Zwierz W: Serum osteoprotegrin (OPG) and receptor activator of nuclear factor kappaB (RANKL) in healthy children and adolescents. J Pediatr Endocrinol Metab. 2009, 22: 1099-1104.CrossRefPubMed
28.
Takayanagi H: Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol. 2009, 5: 667-676. 10.1038/nrrheum.2009.217.CrossRefPubMed
29.
Nakamura M, Udagawa N: Osteoporosis and RANKL signal. Clin Calcium. 2011, 21: 1149-1155.PubMed
30.
Perlot T, Penninger JM: Development and function of murine B cells lacking RANK. J Immunol. 2012, 188: 1201-1205. 10.4049/jimmunol.1102063.CrossRefPubMed
31.
Mun SH, Won HY, Hernandez P, Aguila HL, Lee SK: Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass. J Bone Miner Res. 2013, 28: 948-959. 10.1002/jbmr.1787.CrossRefPubMedPubMedCentral
32.
Droxmeyer HE, Kappes F, Mor-Vaknin N, Legendre M, Kinzforql J, Cooper S, Hangoc G, Markovitz DM: DEK regulates hematopoietic stem engraftment and progenitor cell proliferation. Stem Cells Dev. 2012, 21: 1449-1454. 10.1089/scd.2011.0451.CrossRef
33.
Kroepfl JM, Pekovits K, Stelzer I, Fuchs R, Zelzer S, Hofmann P, Sedlmayr P, Dohr G, Wallner-Liebmann S, Domej W, Muller W: Exercise increases the frequency of circulating hematopoietic progenitor cells, but reduces hematopoietic colony-forming capacity. Stem Cells Dev. 2012, 21: 2915-2925. 10.1089/scd.2012.0017.CrossRefPubMed
34.
He Y, Rhodes SD, Chen S, Wu X, Yuan J, Yang X, Jiang L, Li X, Takahashi N, Xu M, Mohammad KS, Guise TA, Yang FC: c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions. PLoS One. 2012, 7: e46900-10.1371/journal.pone.0046900.CrossRefPubMedPubMedCentral
35.
Yan D, Gurumurthy A, Wright M, Pfeiler TW, Loboa EG, Everett ET: Genetic background influences fluoride’s effects on osteoclastogenesis. Bone. 2007, 41: 1036-1144. 10.1016/j.bone.2007.07.018.CrossRefPubMedPubMedCentral
36.
Broxmeyer HE, Mejia JA, Hangoc G, Barese C, Dinauer M, Cooper S: SDF-1/CXCL12 enhances in vitro replating capacity of murine and human multipotential and macrophage progenitor cells. Stem Cells Dev. 2007, 16: 589-596. 10.1089/scd.2007.0044.CrossRefPubMed
37.
McHugh KP, Shen Z, Crotti TN, Flannery MR, Fajardo R, Bierbaum BE, Goldring SR: Role of cell-matrix interactions in osteoclast differentiation. Adv Exp Med Biol. 2007, 602: 107-111. 10.1007/978-0-387-72009-8_14.CrossRefPubMed
38.
Wu X, Chen S, Orlando SA, Yuan J, Kim ET, Munugalavadla V, Mali RS, Kapur R, Yang FC: p85α regulates osteoblast differentiation by cross-talking with the MAPK pathway. J Biol Chem. 2011, 286: 13512-13521. 10.1074/jbc.M110.187351.CrossRefPubMedPubMedCentral
39.
Abdallah BM, Ditzel N, Mahmood A, Isa A, Traustadottir GA, Schilling AF, Ruiz-Hidalgo MJ, Laborda J, Amling M, Kassem M: DLK1 is a novel regulator of bone mass that mediates estrogen deficiency-induced bone loss in mice. J Bone Miner Res. 2011, 26: 1457-1471. 10.1002/jbmr.346.CrossRefPubMed
40.
41.
Xiao G, Cheng H, Cao H, Chen K, Tu Y, Yu S, Jiao H, Yang S, Im HJ, Chen D, Chen J, Wu C: Critical role of filamin-binding LIM protein 1 (FBLP-1)/migfilin in regulation of bone remodeling. J Biol Chem. 2012, 287: 21450-21460. 10.1074/jbc.M111.331249.CrossRefPubMedPubMedCentral
42.
Nabavi N, Khandani A, Camirand A, Harrison RE: Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion. Bone. 2011, 49: 965-974. 10.1016/j.bone.2011.07.036.CrossRefPubMed
43.
Boyce BF, Xing L: The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 2007, 5: 98-104. 10.1007/s11914-007-0024-y.CrossRefPubMed
44.
Graham LS, Tintut Y, Parhami F, Kitchen CM, Ivanov Y, Tetradis S, Effros RB: Bone density and hyperlipidemia: the T-lymphocyte connection. J Bone Miner Res. 2010, 25: 2460-2469. 10.1002/jbmr.148.CrossRefPubMedPubMedCentral
45.
46.
Chang SK, Noss EH, Chen M, Gu Z, Townsend K, Grenha R, Leon L, Lee SY, Lee DM, Brenner MB: Cadherin-11 regulates fibroblast inflammation. Proc Natl Acad Sci U S A. 2011, 108: 8402-8407. 10.1073/pnas.1019437108.CrossRefPubMedPubMedCentral
47.
Belibasakis GN, Reddi D, Bostanci N: Porphyromonas gingivalis induces RANKL in T-cells. Inflammation. 2011, 34: 133-138. 10.1007/s10753-010-9216-1.CrossRefPubMed
48.
Vander Mierde D, Scheuner D, Quintens R, Patel R, Song B, Tsukamoto K, Beullens M, Kaufman RJ, Bollen M, Schuit FC: Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells. Endocrinology. 2007, 148: 609-617.CrossRefPubMed
49.
Dey S, Baird TD, Zhou D, Palam LR, Spandau DF, Wek RC: Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J Biol Chem. 2010, 285: 33165-33174. 10.1074/jbc.M110.167213.CrossRefPubMedPubMedCentral
50.
Dou G, Sreekumar PG, Spee C, He S, Ryan SJ, Kannan R, Hinton DR: Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction. Free Radic Biol Med. 2012, 53: 1111-1122. 10.1016/j.freeradbiomed.2012.06.042.CrossRefPubMedPubMedCentral
51.
Hamamura K, Tanjung N, Yokota H: Suppression of osteoclastogenesis through phosphorylation of eukaryotic translation initiation factor 2 alpha. J Bone Miner Metab. 2013, -in press
52.
Takayanagi H: The role of NFAT in osteoclast formation. Ann NY Acad Sci. 2007, 1116: 227-237. 10.1196/annals.1402.071.CrossRefPubMed
53.
He L, Lee J, Jang JH, Sakchaisri K, Hwang J, Cha-Molstad HJ, Kim KA, Ryoo IJ, Lee HG, Kim SO, Soung NK, Lee KS, Kwon YT, Erikson RL, Ahn JS, Kim BY: Osteoporosis regulation by salubrinal through eIF2α mediated differentiation of osteoclast and osteoblast. Cell Signal. 2013, 25: 552-560. 10.1016/j.cellsig.2012.11.015.CrossRefPubMed
54.
Kim K, Kim JH, Lee J, Jin HM, Kook H, Kim KK, Lee SY, Kim N: MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood. 2007, 109: 3253-3259. 10.1182/blood-2006-09-048249.CrossRefPubMed
55.
Zhao B, Takami M, Yamada A, Wang X, Koga T, Hu X, Tamura T, Ozato K, Choi Y, Ivashkiv LB, Takayanagi H, Kamijo R: Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med. 2009, 15: 1066-1071. 10.1038/nm.2007.CrossRefPubMedPubMedCentral
56.
Miyauchi Y, Ninomiya K, Miyamoto H, Sakamoto A, Iwasaki R, Hoshi H, Miyamoto K, Hao W, Yoshida S, Morioka H, Chiba K, Kato S, Tokuhisa T, Saitou M, Toyama Y, Suda T, Miyamoto T: The Blimp1-Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis. J Exp Med. 2010, 207: 751-762. 10.1084/jem.20091957.CrossRefPubMedPubMedCentral
Metadata
Title
Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells
Authors
Hiroki Yokota
Kazunori Hamamura
Andy Chen
Todd R Dodge
Nancy Tanjung
Aysan Abedinpoor
Ping Zhang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2013
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/1471-2474-14-197

Other articles of this Issue 1/2013

BMC Musculoskeletal Disorders 1/2013 Go to the issue

Study protocol

Effects of eye movement desensitization and reprocessing (EMDR) on non-specific chronic back pain: a randomized controlled trial with additional exploration of the underlying mechanisms

Research article

Strength gain through eccentric isotonic training without changes in clinical signs or blood markers

Research article

Evaluation of hand bone loss by digital X-ray radiogrammetry as a complement to clinical and radiographic assessment in early rheumatoid arthritis: results from the SWEFOT trial

Research article

Association of back pain with hypovitaminosis D in postmenopausal women with low bone mass

Research article

Urban versus rural differences in the occurrence of hip fractures in Japan’s Kyoto prefecture during 2008–2010: a comparison of femoral neck and trochanteric fractures

Research article

Subchondral pre-solidified chitosan/blood implants elicit reproducible early osteochondral wound-repair responses including neutrophil and stromal cell chemotaxis, bone resorption and repair, enhanced repair tissue integration and delayed matrix deposition