Dickkopf-1 and Sclerostin Serum Levels in Patients with Systemic Mastocytosis
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Bone involvement, mainly osteoporosis but also osteosclerosis, is frequent in patients with indolent systemic mastocytosis (ISM). The recent characterization of the canonical Wnt/β-catenin pathway in the regulation of bone remodeling provided important insights for our understanding of the pathophysiology of a number of conditions. The regulation of Wnt pathway in bone is predominantly driven by the production of receptor inhibitors such as Dickkopf-1 (DKK1) and sclerostin (SOST). This study aimed to explore if the various bone involvements in patients with ISM might be explained by variations in serum levels of DKK1 and SOST. This is a cross-sectional study in an adult ISM cohort (13 men and 13 women with diagnosed ISM) and fifty-two healthy sex and age-matched controls. Early morning, fasting and venous sampling was obtained in all subjects. The main outcome measures were serum bone-specific alkaline phosphatase (bALP), C-terminal telopeptides of type I collagene (CTX), DKK1, SOST, parathyroid hormone (PTH), bone mineral density, and prevalent vertebral fractures. Mean DKK1 serum levels were about two-folds higher in patients, than in controls (65,0 ± 43.3 vs. 33.1 ± 19.4 pmol/L, respectively; p < 0.001), irrespective of the presence of osteoporotic or diffuse osteosclerotic bone involvement. DKK1 serum levels were positively correlated with PTH and both CTX and bALP. Mean SOST serum levels were not significantly different in patients versus controls, and we did not observe any significant correlation between SOST and any available clinical or laboratory parameters, with the only exception of a positive correlation with age. In conclusion, in our study, we observed that DKK1, but not SOST, serum levels significantly increased in ISM patients with various bone involvements, and correlated with PTH and bone turnover markers. Our results suggest that the Wnt/β-catenin pathway is not primarily involved in the pathophysiology of the array of bone involvement in ISM.
KeywordsMastocytosis DKK1 Sclerostin Wnt Osteoporosis Osteosclerosis
We thank Caterina Fraccarollo for excellent technical assistance. The authors thank Sara Rossini and Vidya Kunnathully who provided editorial assistance.
Conflict of Interest
Maurizio Rossini, Ombretta Viapiana, Roberta Zanotti, Gaia Tripi, Omar Perbellini, Luca Idolazzi, Massimiliano Bonifacio, Silvano Adami, and Davide Gatti have no conflict of interest.
Human and Animal Rights and Informed Consent
The study was approved by the local institutional review board. It was conducted in accordance with the ethics principles of the Declaration of Helsinki and was approved by the local ethics committee. Informed consent was obtained from all patients and control subjects.
- 1.Horny HP, Metcalfe DD, Bennett JM et al (2008) Mastocytosis. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumors of hematopoietic and lymphoid tissues, 4th edn. International Agency for Research and Cancer (IARC), Lyon, pp 54–63Google Scholar
- 2.Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J, Jara-Acevedo M, Teodósio C, García-Cosío M, Bellas C, Orfao A (2009) Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients. J Allergy Clin Immunol 124:514–521CrossRefPubMedGoogle Scholar
- 5.Guillaume N, Desoutter J, Chandesris O, Merlusca L, Henry I, Georgin-Lavialle S, Barete S, Hirsch I, Bouredji D, Royer B, Gruson B, Lok C, Sevestre H, Mentaverri R, Brazier M, Meynier J, Hermine O, Marolleau JP, Kamel S, Damaj G (2013) Bone complications of mastocytosis: a link between clinical and biological characteristics. Am J Med 126(75):e1–e7PubMedGoogle Scholar
- 6.Rabenhorst A, Christopeit B, Leja S, Gerbaulet A, Kleiner S, Forster A, Raap U, Wickenauser C, Hartmann K (2013) Serum levels of bone cytokines are increased in indolent systemic mastocytosis associated with osteopenia or osteoporosis. J Allergy Clin Immunol 132:1234–1237CrossRefPubMedGoogle Scholar
- 8.Rossini M, Zanotti R, Bonadonna P, Artuso A, Caruso B, Schena D, Vecchiato D, Bonifacio M, Viapiana O, Gatti D, Senna G, Riccio A, Passalacqua G, Pizzolo G, Adami S (2011) Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49:880–885CrossRefPubMedGoogle Scholar
- 12.Atkins GJ, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26:1425–1436CrossRefPubMedCentralPubMedGoogle Scholar
- 14.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 68:577–589CrossRefPubMedCentralPubMedGoogle Scholar
- 16.Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M, Morony S, Adamu S, Geng Z, Qiu W, Kostenuik P, Lacey DL, Simonet WS, Bolon B, Qian X, Shalhoub V, Ominsky MS, Zhu KH, Li X, Richards WG (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766CrossRefPubMedGoogle Scholar
- 17.Morvan F, Boulukos K, Cle´ment-Lacroix P, Roman SR, Suc-Royer I, Vayssie`re 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 21:934–945CrossRefPubMedGoogle Scholar
- 19.Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, Castellani L, Bonetto C, Frattini F, Dama A, Martinelli G, Chilosi M, Senna G, Pizzolo G, Zanotti R (2009) Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol 123:680–686CrossRefPubMedGoogle Scholar
- 22.Politou MC, Heath DJ, Rahemtulla A, Szydlo R, Anagnostopoulos A, Dimopoulos MA, Croucher PI, Terpos E (2006) Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 119:1728–1731CrossRefPubMedGoogle Scholar
- 23.Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E, Delimpasi S, Pouli A, Meletis J, Kastritis E, Zervas K, Dimopoulos MA (2012) Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. Int J Cancer 131:1466–1471CrossRefPubMedGoogle Scholar
- 26.Rossini M, Viapiana O, Adami S, Idolazzi L, Zanotti R, Gatti D (2015) Rapid skeletal turnover in radiographic mimic of osteopetrosis might be secondary to systemic mastocytosis. J Bone Miner Res (in press)Google Scholar
- 34.Amrein K, Amrein S, Drexler C, Dimai HP, Dobnig H, Pfeifer K, Tomaschitz A, Pieber TR, Fahrleitner-Pammer A (2012) Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J Clin Endocrinol Metab 97:148–154CrossRefPubMedGoogle Scholar