Osteoporosis is a skeletal disorder characterized by deteriorated bone microarchitecture, compromised bone strength and increased risk of fracture. Osteoporotic fractures and their complications lead to considerable morbidity and mortality, making osteoporosis a major public health problem. Osteoporosis is most commonly associated with increasing age and menopausal decrease in estrogen, but can also occur secondary to underlying chronic illnesses, long-term medications and adverse lifestyle factors.

Bone mineral density is known to be highly heritable. Osteoporosis is commonly considered a polygenic disorder, in which variations in multiple genes determine an individual’s skeletal characteristics and risk of osteoporosis. However, recent advances in genetic studies have identified several new genes and genetic loci that alone can lead to notable skeletal pathology. These monogenic forms of osteoporosis vary greatly in their skeletal and extra-skeletal features, severity, age-of-onset and disease course depending on the underlying genetic defect.

The aim of our group is to identify novel genes involved in the development of osteoporosis and to study the role of previously characterized genes and their variation in osteoporosis.  Our study subjects include patients and families with different genetic forms of severe and early-onset osteoporosis. We use various advanced genetic methods, such as whole-genome and -exome sequencing and genome-wide association studies, and several functional studies to elucidate the molecular mechanisms associated with the pathogenesis of osteoporosis. New information about the genetic causes of osteoporosis enables development of improved diagnostic tools and novel therapeutic methods.

Skeletal dysplasias are a heterogeneous group of mostly monogenic disorders with various skeletal abnormalities. We have studied clinical characteristics and the underlying genetic defects in several conditions. We have reported on several patients with the recessive spondyloocular syndrome caused by novel XYLT2 mutations. Soon after discovery of fibronectin mutations as the cause of spondylometaphyseal dysplasia with “corner fractures”, we reported on novel mutations and expanded the clinical and radiographic phenotype.

In several skeletal dysplasias the underlying cause is unknown and our research aims to identify the disease-causing gene defect and molecular pathology in these disorders. In collaboration with an international consortium we recently identified hypomorphic mutations in TONSL as the cause of SPONASTRIME Dysplasia. SPONASTRIME is a rare skeletal disorder characterized by short stature, facial dysmorphism, and abnormalities in the spine and long bone metaphyses. TONSL is a scaffold protein that interacts with DNA replication and repair factors and plays critical roles in maintenance of genome integrity.

A decade ago in Finland, vitamin D deficiency was common in pregnant women, infants, school children, and in children with chronic illness or frequent fractures. Vitamin D deficiency was associated with low bone mineral density (BMD), as measured by bone densitometry or peripheral quantitative CT (pQCT), even in newborns, and with unfavorable bone histology. However, based on our recent studies, vitamin D status has improved and is generally sufficient in pregnant women and newborns, although certain risk groups for vitamin deficiency still exist. This public health improvement is mainly due to increased vitamin D food fortification, updated vitamin D recommendations and public awareness. We have carried out four vitamin D intervention studies which have substantially added our understanding of this prehormone vitamin D.

Currently, we are conducting a follow-up study for our large-scale vitamin D intervention in infants study (VIDI). VIDI children are now 6 to 7 years of age. In near future we will learn more about impact of vitamin D in early childhood to later health outcomes.

 

Obesity is a complex disorder with various contributing genetic and environmental factors. Recent scientific discoveries show that the skeleton also plays an important role in whole-body homeostasis by secreting hormones that participate in energy metabolism and appetite regulation. The genetic causes and mechanisms for severe childhood obesity are still incompletely understood. It is acknowledged that obesity in some individuals and families could be a consequence of rare genetic variants with strong effect – these rare variants might be population specific. We aim to identify new obesity-related genetic variants and disease-causing gene mutations and determine their association with clinical manifestations in families with childhood-onset severe obesity. The study will increase our understanding of the pathogenesis of obesity and provide new tools for early diagnosis and targeted prevention.

Bone health is often compromised in children with leukemia, especially in acute lymphoblastic leukemia (ALL), the most common malignancy in childhood. The most important bone complications, osteoporosis and osteonecrosis, are well known, but their pathomechanisms in childhood leukemia remain incompletely understood. Therefore, this study aims to shed light on the tissue-level pathology underlying skeletal complications in childhood leukemia.

In the ongoing LELU study, all children diagnosed with ALL or acute myeloid leukemia (AML) at Children’s Hospital, Helsinki University Hospital between 2019 and 2021 will be provided the opportunity to participate in the study. The patients will undergo initial clinical evaluation and sample collection at the time of diagnosis, and are then followed throughout until the end of treatment. Long-term follow up will continue at least 5 years after completion of leukemia treatment.

We will use innovative techniques to analyze the routine samples taken for diagnostic purposes: bone marrow aspirate, bone marrow biopsy and blood. Bone structural and functional characteristics will be studied with several novel methods, including quantitative backscattered electron imaging and microRNA panels. Bone characteristics and their changes during treatment are correlated with patient and disease characteristics. Skeletal complications can significantly impair the quality of life in childhood leukemia survivors, despite the otherwise excellent outcome and high survival rate (up to 90 %). Therefore, the ultimate aim of the project is to gain better understanding of the tissue-level changes in bone structure and function to enable development of targeted prevention and treatment strategies for bone complications in childhood leukemia.

Principal investigator: Pauliina Utriainen

 

In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), mutations in the autoimmune regulator gene (AIRE) lead to failure of negative selection of autoreactive T cells and to impaired function of regulatory T cells. Parathyroid and adrenal insufficiencies are the most common endocrinopathies that usually manifest during childhood, but new manifestations appear throughout life.

The national cohort of 98 Finnish patients with APECED, followed since the early 1970s, forms the unique basis of the study. In our ongoing studies, we have a special focus on gonadal functions, bone health, and crosstalk between immune functions and bone. Our mission is to generate, integrate, and interpret clinical information together with the data on molecular and cellular pathology. We collaborate nationally and internationally. Research results will expand our knowledge on disease mechanisms in APECED and the functions of AIRE. The results can be translated into improved care of the patients affected by this rare inherited disease with unpredictable and often severe course.

In addition to mutations in AIRE, other genetic defects may underline primary adrenal insufficiency (PAI). Our ongoing studies aim to describe the incidence of childhood-onset PAI in Finland and to find genetic causes of PAI in these patients.

Principal investigator: Saila Laakso

Cartilage-hair hypoplasia (CHH) is a rare skeletal dysplasia belonging to the Finnish Disease Heritage. Features of CHH include short stature, immunodeficiency, anemia, and increased incidence of Hirschsprung disease and malignancy. 

Previous research has benefited from an exceptionally large number of patients with CHH living in Finland. These landmark studies substantially expanded our knowledge of CHH and led to the discovery of the genetic defect underlying this disease. Our recent studies have described numerous novel findings adding to our understanding of the pathogenesis, immunologic characteristics, disease course and prognosis in CHH.

Recruitment to immunologic studies is opened and our ongoing research projects cover different areas of CHH, such as dental health, malignancies, as well as genetic factors contributing to severe disease course.

Principal investigator: Svetlana Vakkilainen

WNT1 osteoporosis, first described by our research group in 2013, is rare form of monogenic osteoporosis caused by pathogenic variations in the WNT1-gene. WNT1 is a key ligand to the WNT pathway in bone and its aberrant signaling leads to decreased bone formation and low bone mineral density. Patients with heterozygous mutations present with early-onset and severe osteoporosis with multiple long-bone and vertebral compression fractures, kyphotic stature and loss of adult height, whereas homozygous mutations lead to a more severe osteogenesis imperfecta with short stature and long-bone deformities.

To date, WNT1 osteoporosis is still extremely rare and many of its clinical and molecular characteristics remain largely unknown. We have therefore continued our studies to better understand its skeletal features, extra-skeletal complications and the underlying molecular changes. We use several clinical examinations, such as magnetic resonance imaging and bone biopsy histomorphometry and immunohistochemistry, translational assays, such as biomarker and microRNA assays, and functional approaches, such as cell cultures. Our main aim is to better define the pathological mechanisms in bone and other tissues behind WNT1-related skeletal disorders to improve current means of diagnosis, treatment and follow-up.

Principal investigator: Riikka Mäkitie

PLS3 osteoporosis is a rare form of X-linked osteoporosis resulting from abnormal function of Plastin 3, encoded by the PLS3-gene. The disease has an early onset and can progress with increasing age, resulting in severe complications by early adulthood. Due its X-chromosomal inheritance, mutation-positive males are typically more severely affected presenting with low bone mineral density and subsequent multiple peripheral and spinal compression fractures already in childhood. The phenotype in mutation-positive females is usually milder but can vary from subclinical osteopenia to osteoporosis with fragility fractures.

Although, to date, several PLS3 mutation-positive patients have been identified worldwide, many of the clinical and molecular features of PLS3 osteoporosis remain incompletely characterized. We have therefore continued our investigations with various clinical and translational studies. We use several clinical examinations, such as magnetic resonance imaging and bone biopsy histomorphometry and immunohistochemistry, translational assays, such as biomarker and microRNA assays, and functional approaches, such as cell cultures. Our main goal is to better understand the pathomechanisms underlying PLS3-related bone diseases, to ultimately help improve our current means of diagnosis and treatment.

Principal investigator: Riikka Mäkitie

Calvarial doughnut lesions with bone fragility (CDL) is a rare autosomal dominant skeletal disorder characterized by low bone mineral density, increased spinal and peripheral fractures, and sclerotic doughnut-shaped lesions in the cranial bones. By studying six families with rare skeletal phenotype and osteoporosis, we identified the causative gene, Sphingomyelin Synthase 2 (SGMS2), for CDL. SGMS2 gene encodes a plasma membrane-resident protein that functions in sphingolipid metabolism. Patients carrying mutated forms of SGMS2 gene presented with a spectrum of clinical features ranging from isolated childhood-onset osteoporosis to severe spondylometaphyseal dysplasia with neonatal fractures and marked cranial hyperostosis. In addition to skeletal features, several patients had neurological manifestations. Our findings link plasma membrane-bound sphingomyelin metabolism to skeletal homeostasis through yet unknown mechanisms. Ongoing SGMS2 functional studies through national and international collaborations aim to resolve mechanisms in sphingolipid metabolic pathway that contribute to bone strength and mineralization. The ultimate aim is to increase understanding of biochemical and molecular processes underlying skeletal homeostasis and identify novel therapeutic targets to improve bone health.

Principal investigator: Minna Pekkinen