Biomarkers in WNT1 and PLS3 osteoporosis:​ altered concentrations of DKK1 and FGF23

Mäkitie, Riikka E.; Kämpe, Anders; Costantini, Alice; Alm, Jessica J.; Magnusson, Per; Mäkitie, Outi

Affiliations

¹Faculty of Medicine, Folkhälsan Institute of Genetics and Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland

²Molecular Endocrinology Laboratory, Department of Medicine, Hammersmith Campus, Imperial College London, London, UK

³Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

⁴Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden

⁵Department of Clinical Chemistry, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

⁶Children’s Hospital and Pediatric Research Center, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland

Abstract and keywords

Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease‐specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/β‐catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early‐onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf‐1 (DKK1), sclerostin, and intact and C‐terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation‐positive subjects. Findings were compared with 34 healthy mutation‐negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation‐positive subjects compared with WNT1 mutation‐positive subjects (p p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C‐terminal FGF23 were significantly elevated in WNT1 mutation‐positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis.

Keywords: DICKKOPF‐1; FIBROBLAST GROWTH FACTOR 23; OSTEOPOROSIS; PLS3; SCLEROSTIN; WNT SIGNALING

Links

DOI: 10.1002/jbmr.3959

PubMed: 31968132

WoS: 000512486900001

History

Received: 2019-06-24

Revised: 2020-01-3

Accepted: 2020-01-8

Online: 2020-02-11

Cited Works (5)

Year	Entry
2014	McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster J-Y, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang Y-C, Libanati C, Bone HG. Romosozumab in postmenopausal women with low bone mineral density. NEJM. January 30, 2014;370(5):412-420.
2001	Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den J Ende, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet. March 1, 2001;10(5):537-543.
2013	Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. February 2013;19(2):179-192.
2001	Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GCM, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard M-J, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. November 16, 2001;107(4):513-523.
2016	Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, Hofbauer LC, Lau E, Lewiecki EM, Miyauchi A, Zerbini CAF, Milmont CE, Chen L, Maddox J, Meisner PD, Libanati C, Grauer A. Romosozumab treatment in postmenopausal women with osteoporosis. NEJM. October 20, 2016;375(16):1532-1543.

Cited By (5)

Year	Entry
2021	Zhang Y, Wang X, Huang X, Shen L, Zhang L, Shou D, Fan X. Transcriptome sequencing profiling identifies miRNA-331-3p as an osteoblast-specific miRNA in infected bone nonunion. Bone. February 2021;143:115619.
2021	Fratzl-Zelman N, Wesseling-Perry K, Mäkitie RE, Blouin S, Hartmann MA, Zwerina J, Välimäki V-V, Laine CM, Välimäki MJ, Pereira RC, Mäkitie O. Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations. Bone. May 2021;146:115900.
2020	Mäkitie RE, Hackl M, Weigl M, Frischer A, Kämpe A, Costantini A, Grillari J, Mäkitie O. Unique, gender‐dependent serum microRNA profile in PLS3 gene‐related osteoporosis. J Bone Miner Res. October 2020;35(10):1962-1973.
2022	Costantini A, Mäkitie RE, Hartmann MA, Fratzl-Zelman N, Zillikens MC, Kornak U, Søe K, Mäkitie O. Early-onset osteoporosis: rare monogenic forms elucidate the complexity of disease pathogenesis beyond type I collagen. J Bone Miner Res. September 2022;37(9):1623-1641.
2023	Simic MK, Mohanty ST, Xiao Y, Cheng TL, Taylor VE, Charlat O, Croucher PI, McDonald MM. Multi-targeting DKK1 and LRP6 prevents bone loss and improves fracture resistance in multiple myeloma. J Bone Miner Res. June 2023;38(6):814-828.