Genetic Determinants of Osteoporosis
Our group aims to identify new genetic causes and clinical manifestations in osteoporosis and skeletal dysplasias and to study the role of previously characterized genes and their variation in metabolic bone diseases. By learning more about the genetic causes it is possible to develop new tools for effective screening and early treatment
We have identified several large families with inherited, childhood-onset osteoporosis, presenting with multiple peripheral and spinal compression fractures by early adulthood. In many of the families, we have identified the disease-causing gene variant. We have described a heterozygous missense mutation in WNT1 that leads to aberrant WNT signaling and causes an abnormal skeletal phenotype in children and young adults, and several mutations in the X-chromosomal PLS3, causing severe osteoporosis in boys and men. Additionally, we have recently identified heterozygous pathogenic variants in SGMS2 leading to altered sphingolipid metabolism and causing through yet unknown mechanism childhood-onset osteoporosis with or without complex skeletal dysplasia. By exome and whole-genome sequencing studies we have identified several new genes associated with early-onset osteoporosis and studies are ongoing in other families with unidentified genetic causes.
Further studies have revealed altered levels of bone biomarkers FGF23 and DKK1 in WNT1-and PLS3-related osteoporosis, respectively, as well as altered microRNA profiles in these monogenic forms of osteoporosis. These results provide new insights to the mechanisms behind the skeletal pathologies. Currently, we have ongoing in vitro and in vivo studies on WNT1, PLS3, and SGMS2, through national and international collaborations.
We have also studied the role of LRP6, FGF23, WNT16, CRTAP, and several other genes in early-onset osteoporosis and have investigated the effect of genetic variation on bone mineral density and mineral homeostasis in children and adolescents. In addition, we showed that genetic variation in the vitamin D binding protein affects vitamin D status and the response to vitamin D supplementation in infants. Furthermore, we have several other ongoing genetic studies on childhood obesity and bone metabolism, short stature, skeletal dysplasias, and endocrinopathies. For instance, we have detected a novel mutation in MYT1L in a patient with severe early-onset obesity and identified rare genetic variants that are linked to appetite control and hypothalamic development in early-onset severe obesity.
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Group Leader
Outi Mäkitie, MD, PhD, Professor
Senior Scientist
Minna Pekkinen, PhD, Docent, Administrative Group Leader
Pauliina Utriainen, MD, PhD, Docent
Post-Doctoral Scientists
Saila Laakso, MD, PhD
Petra Loid, MD, PhD
Mari Muurinen, MD, PhD
Riikka Mäkitie, MD, PhD
Kirsi Määttä, MSc, PhD
Svetlana Vakkilainen, MD, PhD
Graduate Students
Joonatan Borchers, MD
Maria Enlund-Cerullo, MD
Laura Koljonen, MSc
Petra Loid, MD
Eetu Pello, MD
Sandra Pihlström, MSc
Undergraduate Students
Maria Heinonen, BSc
Viivi Saari, BM
Staff
Mira Aronen, Biomedical Laboratory Scientist
Ekaterina Pylsy, Biomedical Laboratory Scientist
Iuliia Savenko, MSc, Laboratory Coordinator
Päivi Turunen, RN, Research administrative coordinator
Koljonen, L., Enlund-Cerullo, M., Hauta-Alus, H., Holmlund-Suila, E., Valkama, S., Rosendahl, J., Andersson, S., Pekkinen, M., & Mäkitie, O. (2021). Phosphate Concentrations and Modifying Factors in Healthy Children From 12 to 24 Months of Age. The Journal of clinical endocrinology and metabolism, 106(10), 2865–2875. https://doi.org/10.1210/clinem/dgab495
LAINE, C.M., LAINE, T., JOENG, K.S., CAMPEAU, P.M., KIVIRANTA, R., TARKKONEN, K., GROVER, M., LU, J.T., PEKKINEN, M., WESSMAN, M., HEINO, T.J., NIEMINEN-PIHALA, V., ARONEN, M., KRÖGER, H., COLE, W.G., LEHESJOKI, A., NEVAREZ, L., KRAKOW, D., CURRY, C.J.R., COHN, D.H., GIBBS, R.A., LEE, B.H. and MÄKITIE, O., 2013. WNT1 Mutations in Early-Onset Osteoporosis and Osteogenesis Imperfecta. The New England Journal of Medicine, 368(19), pp. 1809-1816.
PEKKINEN, M., TERHAL, P.A., BOTTO, L.D., HENNING, P., MÄKITIE, R.E., ROSCHGER, P., JAIN, A., KOL, M., KJELLBERG, M.A., PASCHALIS, E.P., VAN GASSEN, K., MURRAY, M., BAYRAK-TOYDEMIR, P., MAGNUSSON, M.K., JANS, J., KAUSAR, M., CAREY, J.C., SOMERHARJU, P., LERNER, U.H., VESA, O.M., KLAUSHOFER, K., HOLTHUIS, J.C. and MÄKITIE, O., 2019. Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2. JCI Insight, 4(7),.
MÄKITIE, R.E., HENNING, P., JIU, Y., KÄMPE, A., KOGAN, K., COSTANTINI, A., VÄLIMÄKI, V.V., MEDINA-GOMEZ, C., PEKKINEN, M., SALUSKY, I.B., SCHALIN-JÄNTTI, C., HAANPÄÄ, M.K., RIVADENEIRA, F., BASSETT, J.H.D., WILLIAMS, G.R., LERNER, U.H., PEREIRA, R.C., LAPPALAINEN, P., MÄKITIE, O. 2021. An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility. JBMR Plus. 2021 Jun 7;5(7):e10509. doi: 10.1002/jbm4.10509.
MÄKITIE, R.E., BLOUIN, S., VÄLIMÄKI, V.V., PIHLSTRÖM, S., MÄÄTTÄ, K., PEKKINEN, M., FRATZL-ZELMAN, N., MÄKITIE, O., HARTMANN, M. 2021. Abnormal bone tissue organization and osteocyte lacuno–canalicular network in early-onset osteoporosis due to SGMS2 mutations. JBMR Plus. 2021 Aug doi: 10.1002/jbm4.10537
LAAKSO, S., BORCHERS, J., TOIVIAINEN-SALO, S., PEKKINEN, M. and MÄKITIE, O., 2020. Severe Phenotype of APECED (APS1) Increases Risk for Structural Bone Alterations. Frontiers in endocrinology, 11, pp. 109.
LOID, P., MUSTILA, T., MÄKITIE, R.E., VILJAKAINEN, H., KÄMPE, A., TOSSAVAINEN, P., LIPSANEN-NYMAN, M., PEKKINEN, M. and MÄKITIE, O., 2020. Rare Variants in Genes Linked to Appetite Control and Hypothalamic Development in Early-Onset Severe Obesity. Frontiers in endocrinology, 11, pp. 81.
MÄKITIE, R.E., KÄMPE, A., COSTANTINI, A., ALM, J.J., MAGNUSSON, P. and MÄKITIE, O., 2020. Biomarkers in WNT1 and PLS3 Osteoporosis: Altered Concentrations of DKK1 and FGF23. Journal of Bone and Mineral Research, 35(5), pp. 901-912.
ENLUND-CERULLO, M., KOLJONEN, L., HOLMLUND-SUILA, E., HAUTA-ALUS, H., ROSENDAHL, J., VALKAMA, S., HELVE, O., HYTINANTTI, T., VILJAKAINEN, H., ANDERSSON, S., MÄKITIE, O. and PEKKINEN, M., 2019. Genetic Variation of the Vitamin D Binding Protein Affects Vitamin D Status and Response to Supplementation in Infants. The Journal of Clinical Endocrinology & Metabolism, 104(11), pp. 5483-5498.
KÄMPE, A., ENLUND-CERULLO, M., VALKAMA, S., HOLMLUND-SUILA, E., ROSENDAHL, J., HAUTA-ALUS, H., PEKKINEN, M., ANDERSSON, S. and MÄKITIE, O., 2019. Genetic variation in GC and CYP2R1 affects 25-hydroxyvitamin D concentration and skeletal parameters: A genome-wide association study in 24-month-old Finnish children. PLoS genetics, 15(12), pp. e1008530.
LOID, P., MÄKITIE, R., COSTANTINI, A., VILJAKAINEN, H., PEKKINEN, M. and MÄKITIE, O., 2018. A novel MYT1L mutation in a patient with severe early‐onset obesity and intellectual disability. American Journal of Medical Genetics Part A, 176(9), pp. 1972-1975.
MÄKITIE, R.E., HACKL, M., NIINIMÄKI, R., KAKKO, S., GRILLARI, J. and MÄKITIE, O., 2018. Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling. The Journal of Clinical Endocrinology & Metabolism, 103(5), pp. 1985-1996.
KOSTJUKOVITS, S., DEGERMAN, S., PEKKINEN, M., KLEMETTI, P., LANDFORS, M., ROOS, G., TASKINEN, M. and MÄKITIE, O., 2017. Decreased telomere length in children with cartilage-hair hypoplasia. Journal of Medical Genetics, 54(5), pp. 365-370.
MÄKITIE, R.E., HAANPÄÄ, M., VALTA, H., PEKKINEN, M., LAINE, C.M., LEHESJOKI, A., SCHALIN‐JÄNTTI, C. and MÄKITIE, O., 2016. Skeletal Characteristics of WNT1 Osteoporosis in Children and Young Adults. Journal of Bone and Mineral Research, 31(9), pp. 1734-1742.
LAINE, C.M., WESSMAN, M., TOIVIAINEN‐SALO, S., KAUNISTO, M.A., MÄYRÄNPÄÄ, M.K., LAINE, T., PEKKINEN, M., KRÖGER, H., VÄLIMÄKI, V., VÄLIMÄKI, M.J., LEHESJOKI, A. and MÄKITIE, O., 2015. A Novel Splice Mutation in PLS3 Causes X‐linked Early Onset Low‐Turnover Osteoporosis. Journal of Bone and Mineral Research, 30(3), pp. 510-518.
PEKKINEN, M., LAINE, C.M., MÄKITIE, R., LEINONEN, E., LAMBERG-ALLARDT, C., VILJAKAINEN, H. and MÄKITIE, O., 2014. FGF23 gene variation and its association with phosphate homeostasis and bone mineral density in Finnish children and adolescents. Bone, 71, pp. 124-130.
LAINE, C.M., KOLTIN, D., SUSIC, M., VARLEY, T.L., DANEMAN, A., MOINEDDIN, R., COLE, W.G., MÄKITIE, O. and SOCHETT, E., 2012. Primary osteoporosis without features of OI in children and adolescents: Clinical and genetic characteristics. American Journal of Medical Genetics Part A, 158A(6), pp. 1252-1261.
MÄYRÄNPÄÄ, M.K., VILJAKAINEN, H.T., TOIVIAINEN‐SALO, S., KALLIO, P.E. and MÄKITIE, O., 2012. Impaired bone health and asymptomatic vertebral compressions in fracture‐prone children: A case‐control study. Journal of Bone and Mineral Research, 27(6), pp. 1413-1424.
Folkhälsan Research Foundation
Academy of Finland
Novo Nordisk Foundation
Sigrid Jusélius Foundation
Foundation for Pediatric Research
Prof. Juha Kere, Prof. Anna-Elina Lehesjoki, Folkhälsan
Doc. Camilla Schalin-Jäntti, Doc. Heikki A. Koistinen, Doc. Sanna Toiviainen-Salo, Doc. Helena Valta, Helsinki University Hospital
Prof. Pertti Panula, Prof. Vesa Olkkonen, Prof. Pentti Somerharju, University of Helsinki
Dr. Markus Hartmann, Ludwig Boltzmann Institute of Osteology, Vienna, Austria
Prof. Harald Jüppner, Massachusetts General Hospital, Boston, USA
Prof. Fernando Rivadeneira, Erasmus University Rotterdam, The Netherlands
Prof. Olle Kämpe, Dr. Tuomas Näreoja, Karolinska Institutet, Sweden
Prof. Renata Pereira University of California, Los Angeles, USA
Prof. Valérie Cormier-Daire, Université Paris Descartes, Paris, France
