Abstract
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.
Similar content being viewed by others
References
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 54–63
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 124:514–521
Rossini M, Zanotti R, Viapiana O et al (2014) Bone involvement and osteoporosis in mastocytosis. Immunol Allergy Clin North Am 34:383–396
Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, Kalogeromitros D (2012) Mast cells and inflammation. Biochim Biophys Acta 1822:21–33
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–e7
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 132:1234–1237
Rossini M, Adami S, Zanotti R, Viapiana O, Idolazzi L, Biondan M, Gatti D (2014) Serum levels of bone cytokines in indolent systemic mastocytosis associated with osteopenia or osteoporosis. J Allergy Clin Immunol 133:933–935
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 49:880–885
Baron R, Rawadi G (2007) Minireview: targeting the Wnt/β-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148:2635–2643
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
Bafico A, Liu G, Yaniv A, Gazit A, Aaronson S (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3:683–686
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 26:1425–1436
Moester MJ, Papapoulos SE, LöwikCW, van Bezooijen RL (2010) Sclerostin: current knowledge and future perspectives. Calcif Tissue Int 87:99–107
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
van Lierop AH, Hamdy NA, van Egmond ME, Bakker E, Dikkers FG, Papapoulos SE (2013) Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res 28:848–854
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 39:754–766
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 21:934–945
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD Jr (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483–2494
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 123:680–686
Kanis JA (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO study group. Osteoporos Int 4:368–381
Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148
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 119:1728–1731
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 131:1466–1471
Atkins GJ, Kostakis P, Pan B, Farrugia A, Gronthos S, Evdokiou A, Harrison K, Findlay DM, Zannettino AC (2003) RANKL expression is related to the differentiation state of human osteoblasts. J Bone Miner Res 18:1088–1098
van Lierop AH, Moester MJ, Hamdy NA, Papapoulos SE (2014) Serum Dickkopf 1 levels in sclerostin deficiency. J Clin Endocrinol Metab 99:E252–E256
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)
Seitz S, Barvencik F, Koehne T, Priemel M, Pogoda P, Semler J, Minne H, Pfeiffer M, Zustin J, Püschel K, Eulenburg C, Schinke T, Amling M (2013) Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis. Osteoporos Int 24:2325–2334
Rossini M, Zanotti R, Viapiana O, Tripi G, Idolazzi L, Biondan M, Orsolini G, Bonadonna P, Adami S, Gatti D (2014) Zoledronic acid in osteoporosis secondary to mastocytosis. Am J Med 127(1127):e1–e4
Viapiana O, Fracassi E, Troplini S, Idolazzi L, Rossini M, Adami S, Gatti D (2013) Sclerostin and DKK1 in primary hyperparathyroidism. Calcif Tissue Int 92:324–329
Gatti D, Viapiana O, Idolazzi L, Fracassi E, Rossini M, Adami S (2011) The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab 96:1555–1559
Rossini M, Gatti D, Adami S (2013) Involvement of WNT/b-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int 93:121–132
Mirza FS, Padhi ID, Raisz LG, Lorenzo JA (2010) Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 95:1991–1997
Ardawi MS, Al-Kadi HA, Rouzi AA, Qari MH (2011) Determinants of serum sclerostin in healthy pre- and postmenopausal women. J Bone Mineral Res 26:2812–2822
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 97:148–154
Acknowledgments
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rossini, M., Viapiana, O., Zanotti, R. et al. Dickkopf-1 and Sclerostin Serum Levels in Patients with Systemic Mastocytosis. Calcif Tissue Int 96, 410–416 (2015). https://doi.org/10.1007/s00223-015-9969-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-015-9969-5