Metabolic Bone Diseases

Our team studies genetic defects and molecular mechanisms underlying skeletal disorders, with main focus on early-onset primary osteoporosis, skeletal dysplasias, and vitamin D.

Osteoporosis is a skeletal disorder characterized by reduced bone mineral density, compromised bone strength, and susceptibility to fractures. Genetic factors play a major role in disease susceptibility and characteristics. Due to the silent development of the disease, diagnosis is usually made at adult age when the severe consequences of bone fragility emerge, but the disease often has its onset in childhood. The pathomolecular mechanisms leading to disease in young patients with novel forms of osteoporosis have yet to be fully explored. Moreover, evidence on efficacy of currently available treatments for osteoporosis in children and young adults is still lacking.

Skeletal dysplasias encompass a group of more than 400 monogenic diseases with significant skeletal involvement. Due to the rarity of these conditions and their broad clinical and genetic heterogeneity, many families still lack a genetic diagnosis and novel gene defects remain to be characterized. The lack of pharmacological treatment options for most subtypes of skeletal dysplasia is a further challenge and merits better understanding of disease mechanisms.

Vitamin D deficiency is a significant health concern in several populations. Recent studies by others and us have shown that especially children with a chronic illness, including childhood cancer, are at high risk of vitamin D deficiency. This in turn may have significant health consequences, including impaired skeletal health.

By combining genetic testing, primarily next-generation sequencing, and in vitro functional studies our aims are:

1. To characterize novel variants and genes involved in skeletal development and maintenance. We have collected detailed clinical information and genomic DNA from several families affected by early-onset osteoporosis and some subtypes of skeletal dysplasias with unknown genetic causes. By applying whole-genome sequencing, we aim to pinpoint the genetic cause of disease in these families. Once a novel candidate variant is identified, molecular studies at RNA and protein levels are carried out to elucidate the biological effects of the identified gene variants.

2. To decipher the role of novel and previously identified gene defects. Cell biological disease mechanisms are investigated by studying patient-derived cells. Skin-derived fibroblasts from several families with rare skeletal diseases as well as bone marrow from a handful of patients have been collected. Different in vitro assays are carried out to study the pathomechanisms based on specific research questions and function of the investigated gene. Part of our research focus on skeletal progenitors (mesenchymal stromal cells, MSCs) and their role in skeletal cell differentiation and function in metabolic bone diseases.

3. To elucidate the role of Vitamin D in bone health. We have an ongoing large-scale vitamin D intervention study in infants (VIDI) that aims to find means to optimize vitamin D status in young children. Genetic data from this cohort allow us to perform genome-wide association studies to search for novel genetic loci associated with circulating vitamin D levels and bone health in a prospective longitudinal setting.

Significance: By identifying novel disease-gene associations and by understanding the disease pathogenesis we will establish means for early diagnosis, and better prevention and treatment of childhood-onset skeletal disorders.

Team members