Endocrine Abstracts (2019) 65 IN1.1 | DOI: 10.1530/endoabs.65.IN1.1

Identifying new skeletal disease

Outi Mäkitie


University of Helsinki, Helsinki, Finland


Metabolic bone diseases encompass a large spectrum of disorders of bone strength, bone growth, or bone structure. Most of the disorders are caused by genetic defects and have onset prenatally or in childhood. The International classification of genetic skeletal disorders includes >450 disorders divided into 40 subgroups based on their clinical, radiographic and genetic features. The individual disorders are rare but collectively result in significant morbidity and pose a challenge to health care system. Underlying pathology remains inadequately understood in most of these disorders and optimal therapy is often undefined. In order to gain further understanding of the molecular mechanisms leading to the clinical phenotype, research is needed to identify genetic defects and cellular pathology in rare bone diseases. In monogenic forms of osteoporosis, bone fragility is caused by a single mutation in a gene that has a major role in the skeleton. Our research group has identified two novel genetic forms of osteoporosis, caused by WNT1and SGMS2 mutations. WNT1 is a key ligand for the WNT-signaling pathway in the regulation of bone mass and homozygous or heterozygous WNT1 mutations lead to childhood-onset and progressive skeletal fragility. SGMS2 mutations lead to disturbed sphingolipid metabolism, skeletal fragility and defective bone mineralization. The WNT signaling pathway has already proved to be an important drug target whereas the role of sphingolipid metabolism in bone homeostasis remains to be further elucidated. Ongoing genetic studies in several other families with early-onset osteoporosis suggest the presence of multiple other monogenic forms of osteoporosis in which one gene defect plays a major role and other gene variants and life-style factors only play a minor role. Discovery of new genes and unveiling the pathogenetic mechanisms underlying metabolic bone diseases enable development of targeted diagnostic, preventive and therapeutic methods and expands our knowledge on skeletal physiology and pathology.

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