Abstract
Osteocytes are embedded in bone matrices and are connected to each other to respond to mechanical loading on bone. Recent studies have demonstrated the roles of mechanical loading in bone accrual. Bone responds to mechanical loading by decreasing the expression of sclerostin, an inhibitor of Wnt/β-catenin signals, in osteocytes. This increases bone mass because the activation of Wnt/β-catenin signals in bone microenvironments promotes bone formation and suppresses bone resorption. Thus, in recent years, sclerostin have attracted increasing attention in bone metabolism. However, the regulatory mechanism of sclerostin expression during bone remodeling has not been fully elucidated. In this review, we summarized the regulation of bone formation and resorption by Wnt signals, a Wnt/β-catenin signal inhibitor sclerostin, and molecular mechanisms by which the expression of sclerostin is suppressed by mechanical loading and parathyroid hormone. We also discuss a possibility that osteoclasts suppress the expression of sclerostin during bone remodeling, which in turn, promote bone formation. The effectiveness of an anti-sclerostin antibody with anti-dickkopf-1 antibody for increasing bone mass was discussed.
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References
Sims NA, Martin TJ (2014) Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. Bonekey Rep 3:481
Crane JL, Cao X (2014) Bone marrow mesenchymal stem cells and TGF-beta signaling in bone remodeling. J Clin Invest 124:466–472
Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602
Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309
Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20:345–357
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319
Yasuda H, Shima N, Nakagawa N, Mochizuki SI, Yano K, Fujise N, Sato Y, Goto M, Yamaguchi K, Kuriyama M, Kanno T, Murakami A, Tsuda E, Morinaga T, Higashio K (1998) Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139:1329–1337
Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268
Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, Sato Y, Nakagawa N, Yasuda H, Mochizuki S, Gomibuchi T, Yano K, Shima N, Washida N, Tsuda E, Morinaga T, Higashio K, Ozawa H (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615
Nakamura M, Udagawa N, Matsuura S, Mogi M, Nakamura H, Horiuchi H, Saito N, Hiraoka BY, Kobayashi Y, Takaoka K, Ozawa H, Miyazawa H, Takahashi N (2003) Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption. Endocrinology 144:5441–5449
Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van Hul W, Wan M, Cao X (2009) TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15:757–765
Xian L, Wu X, Pang L, Lou M, Rosen CJ, Qiu T, Crane J, Frassica F, Zhang L, Rodriguez JP, Xiaofeng J, Shoshana Y, Shouhong X, Argiris E, Mei W, Xu C (2012) Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat Med 18:1095–1101
Walker EC, McGregor NE, Poulton IJ, Pompolo S, Allan EH, Quinn JM, Gillespie MT, Martin TJ, Sims NA (2008) Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J Bone Miner Res 23:2025–2032
Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 105:20764–20769
Takeshita S, Fumoto T, Matsuoka K, Park KA, Aburatani H, Kato S, Ito M, Ikeda K (2013) Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Invest 123:3914–3924
Lotinun S, Kiviranta R, Matsubara T, Alzate JA, Neff L, Luth A, Koskivirta I, Kleuser B, Vacher J, Vuorio E, Horne WC, Baron R (2013) Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 123:666–681
Xie H, Cui Z, Wang L, Xia Z, Hu Y et al (2014) PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 20:1270–1278
Zhao C, Irie N, Takada Y, Shimoda K, Miyamoto T, Nishiwaki T, Suda T, Matsuo K (2006) Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab 4:111–121
Joeng KS, Lee YC, Lim J, Chen Y, Jiang MM, Munivez E, Ambrose C, Lee BH (2017) Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J Clin Invest 127:2678–2688
van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Löwik CW (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814
Koide M, Kobayashi Y, Yamashita T, Uehara S, Nakamura M, Hiraoka BY, Ozaki Y, Iimura T, Yasuda H, Takahashi N, Udagawa N (2017) Bone Formation is coupled to resorption via suppression of sclerostin expression by osteoclasts. J Bone Miner Res 32:2074–2086
Miller JR (2002) The Wnts. Genome Biol 3:Reviews3001
Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192
Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S, Nishita M, Marumo K, Martin TJ, Minami Y, Takahashi N (2012) Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 18:405–412
Okamoto M, Udagawa N, Uehara S, Maeda K, Yamashita T, Nakamichi Y, Kato H, Saito N, Minami Y, Takahashi N, Kobayashi Y (2014) Noncanonical Wnt5a enhances Wnt/beta-catenin signaling during osteoblastogenesis. Sci Rep 4:4493
Chen J, Tu X, Esen E, Joeng KS, Lin C, Arbeit JM, Ruegg MA, Hall MN, Ma L, Long F (2014) WNT7B promotes bone formation in part through mTORC1. PLoS Genet 10:e1004145
Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF, Hankenson KD, MacDougald OA (2005) Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci USA 102:3324–3329
Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G (2005) Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 8:751–764
Tu X, Delgado-Calle J, Condon KW, Maycas M, Zhang H, Carlesso N, Taketo MM, Burr DB, Plotkin LI, Bellido T (2015) Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone. Proc Natl Acad Sci USA 112:E478–E486
Uehara S, Udagawa N, Mukai H, Ishihara A, Maeda K, Yamashita T, Murakami K, Nishita M, Nakamura T, Kato S, Minami Y, Takahashi N, Kobayashi Y (2017) Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling. Sci Signal 10:eaan0023
Movérare-Skrtic S, Henning P, Liu X, Nagano K, Saito H et al (2014) Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nat Med 20:1279–1288
Bartscherer K, Pelte N, Ingelfinger D, Boutros M (2006) Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell 125:523–533
Banziger C, Soldini D, Schutt C, Zipperlen P, Hausmann G, Basler K (2006) Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125:509–522
Zhong Z, Zylstra-Diegel CR, Schumacher CA, Baker JJ, Carpenter AC, Rao S, Yao W, Guan M, Helms JA, Lane NE, Lang RA, Williams BO (2012) Wntless functions in mature osteoblasts to regulate bone mass. Proc Natl Acad Sci USA 109:E2197–E2204
Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523
Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C (2005) Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell 8:727–738
Day TF, Guo X, Garrett-Beal L, Yang Y (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739–750
Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589
Balemans W, Ebeling M, Patel N, Van Hul E, Olson P et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543
Balemans W, Patel N, Ebeling M, Van Hul E, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97
Collette NM, Genetos DC, Economides AN, Xie L, Shahnazari M, Yao W, Lane NE, Harland RM, Loots GG (2012) Targeted deletion of Sost distal enhancer increases bone formation and bone mass. Proc Natl Acad Sci USA 109:14092–14097
Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887
Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869
Li X, Ominsky MS, Warmington KS, Morony S, Gong J et al (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588
Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, Hofbauer LC, Lau E, Lewiecki EM, Miyauchi A, Zerbini CA, Milmont CE, Chen L, Maddox J, Meisner PD, Libanati C, Grauer A (2016) Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375:1532–1543
Leupin O, Piters E, Halleux C, Hu S, Kramer I et al (2011) Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function. J Biol Chem 286:19489–19500
Chang MK, Kramer I, Huber T, Kinzel B, Guth-Gundel S, Leupin O, Kneissel M (2014) Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels. Proc Natl Acad Sci USA 111:E5187–E5195
Xiong L, Jung JU, Wu H, Xia WF, Pan JX, Shen C, Mei L, Xiong WC (2015) Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. Proc Natl Acad Sci USA 112:3487–3492
Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C (2002) Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 417:664–667
Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945
Guo J, Liu M, Yang D, Bouxsein ML, Saito H, Galvin RJ, Kuhstoss SA, Thomas CC, Schipani E, Baron R, Bringhurst FR, Kronenberg HM (2010) Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 11:161–171
Glantschnig H, Hampton RA, Lu P, Zhao JZ, Vitelli S et al (2010) Generation and selection of novel fully human monoclonal antibodies that neutralize Dickkopf-1 (DKK1) inhibitory function in vitro and increase bone mass in vivo. J Biol Chem 285:40135–40147
Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615
Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE, Turner CH (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875
Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L (2009) Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 24:1651–1661
Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, Stolina M, Turner CH, Robling AG, Plotkin LI, Bellido T (2011) Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone 50:209–217
Horiuchi K, Amizuka N, Takeshita S, Takamatsu H, Katsuura M, Ozawa H, Toyama Y, Bonewald LF, Kudo A (1999) Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta. J Bone Miner Res 14:1239–1249
Rios H, Koushik SV, Wang H, Wang J, Zhou HM, Lindsley A, Rogers R, Chen Z, Maeda M, Kruzynska-Frejtag A, Feng JQ, Conway SJ (2005) Periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype. Mol Cell Biol 25:11131–11144
Bonnet N, Standley KN, Bianchi EN, Stadelmann V, Foti M, Conway SJ, Ferrari SL (2009) The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. J Biol Chem 284:35939–35950
Bonnet N, Conway SJ, Ferrari SL (2012) Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin. Proc Natl Acad Sci USA 109:15048–15053
Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (1993) Anabolic actions of parathyroid hormone on bone. Endocr Rev 14:690–709
Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441
Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37:148–158
Kramer I, Loots GG, Studer A, Keller H, Kneissel M (2010) Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res 25:178–189
Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, Keller H (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22:1957
Wein MN, Spatz J, Nishimori S, Doench J, Root D, Babij P, Nagano K, Baron R, Brooks D, Bouxsein M, Pajevic PD, Kronenberg HM (2015) HDAC5 controls MEF2C-driven sclerostin expression in osteocytes. J Bone Miner Res 30:400–411
Berdeaux R, Goebel N, Banaszynski L, Takemori H, Wandless T, Shelton GD, Montminy M (2007) SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nat Med 13:597–603
Parra M, Verdin E (2010) Regulatory signal transduction pathways for class IIa histone deacetylases. Curr Opin Pharmacol 10:454–460
Wein MN, Liang Y, Goransson O, Sundberg TB, Wang J et al (2016) SIKs control osteocyte responses to parathyroid hormone. Nat Commun 7:13176
Powell WF Jr, Barry KJ, Tulum I, Kobayashi T, Harris SE, Bringhurst FR, Pajevic PD (2011) Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses. J Endocrinol 209:21–32
Delgado-Calle J, Tu X, Pacheco-Costa R, McAndrews K, Edwards R, Pellegrini GG, Kuhlenschmidt K, Olivos N, Robling A, Peacock M, Plotkin LI, Bellido T (2017) Control of bone anabolism in response to mechanical loading and PTH by distinct mechanisms downstream of the PTH receptor. J Bone Miner Res 32:522–535
Walker EC, McGregor NE, Poulton IJ, Solano M, Pompolo S, Fernandes TJ, Constable MJ, Nicholson GC, Zhang JG, Nicola NA, Gillespie MT, Martin TJ, Sims NA (2010) Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J Clin Invest 120:582–592
Bellido T (2014) Osteocyte-driven bone remodeling. Calcif Tissue Int 94:25–34
Goldring SR (2015) The osteocyte: key player in regulating bone turnover. RMD Open 1:e000049
Prideaux M, Findlay DM, Atkins GJ (2016) Osteocytes: the master cells in bone remodelling. Curr Opin Pharmacol 28:24–30
Masuki H, Li M, Hasegawa T, Suzuki R, Ying G, Zhusheng L, Oda K, Yamamoto T, Kawanami M, Amizuka N (2010) Immunolocalization of DMP1 and sclerostin in the epiphyseal trabecule and diaphyseal cortical bone of osteoprotegerin deficient mice. Biomed Res 31:307–318
Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG (2009) Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 24:153–161
Reid IR, Miller PD, Brown JP, Kendler DL, Fahrleitner-Pammer A, Valter I, Maasalu K, Bolognese MA, Woodson G, Bone H, Ding B, Wagman RB, San Martin J, Ominsky MS, Dempster DW, Denosumab Phase 3 Bone Histology Study G (2010) Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res 25:2256–2265
Gatti D, Viapiana O, Fracassi E, Idolazzi L, Dartizio C, Povino MR, Adami S, Rossini M (2012) Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab. J Bone Miner Res 27:2259–2263
Anastasilakis AD, Polyzos SA, Gkiomisi A, Bisbinas I, Gerou S, Makras P (2013) Comparative effect of zoledronic acid versus denosumab on serum sclerostin and dickkopf-1 levels of naive postmenopausal women with low bone mass: a randomized, head-to-head clinical trial. J Clin Endocrinol Metab 98:3206–3212
Witcher PC, Miner SE, Horan DJ, Bullock WA, Lim KE, Kang KS, Adaniya AL, Ross RD, Loots GG, Robling AG (2018) Sclerostin neutralization unleashes the osteoanabolic effects of Dkk1 inhibition. JCI Insight. https://doi.org/10.1172/jci.insight.98673
Tu X, Delgado-Calle J, Condon KW, Maycas M, Zhang H, Carlesso N, Taketo MM, Burr DB, Plotkin LI, Bellido T (2015) Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone. Proc Natl Acad Sci USA 112:E478–E486
Colditz J, Thiele S, Baschant U, Niehrs C, Bonewald LF, Hofbauer LC, Rauner M (2018) Postnatal skeletal deletion of Dickkopf-1 increases bone formation and bone volume in male and female mice, despite increased sclerostin expression. J Bone Miner Res. https://doi.org/10.1002/jbmr.3463
Florio M, Gunasekaran K, Stolina M, Li X, Liu L et al (2016) A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 7:11505
Acknowledgements
This work was supported in part by Grants-in-Aid 18H02980 (M.K.), 16H02691 (Y. K.), 18H05388 (Y. K.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Koide, M., Kobayashi, Y. Regulatory mechanisms of sclerostin expression during bone remodeling. J Bone Miner Metab 37, 9–17 (2019). https://doi.org/10.1007/s00774-018-0971-7
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DOI: https://doi.org/10.1007/s00774-018-0971-7