Endocrine Abstracts (2018) 59 S4.3 | DOI: 10.1530/endoabs.59.S4.3

Rare bone disorders: New genes, biology and therapeutic targets

Outi Makitie


Children’s Hospital, University of Helsinki, Helsinki, Finland.


Genetic discoveries in patients and families with rare bone disorders have highlighted the complexity of molecular mechanisms and cellular pathways governing normal bone development and homeostasis. More than 400 different forms of skeletal dysplasia have been described. Most of them result from single-gene defects, involving genes that are of major importance for a particular cellular event in skeletal development. Studies aiming to identify the involved pathways can enable development of new therapeutic strategies for skeletal disorders. Previous studies have identified several forms of monogenic bone fragility that are directly or indirectly related to type I collagen. Importantly, other forms also exist, often with unique skeletal and extra-skeletal features and with variable inheritance patterns. The discovery of LRP5 mutations in osteoporosis-pseudoglioma syndrome and in early-onset osteoporosis first indicated that the WNT-signalling pathway plays an important role in bone mass accrual. Several other studies thereafter, including our discovery of WNT1 mutations in early-onset osteoporosis, have further highlighted the pathway’s significance in various disorders of low and high bone mass and provided evidence for the potential of WNT-targeted therapies in osteoporosis treatment. The X-chromosomal osteoporosis caused by PLS3 gene mutations is another example of novel monogenic forms of osteoporosis. PLS3 osteoporosis affects especially males and leads to severe progressive spinal osteoporosis; even females carrying the mutation may develop symptomatic osteoporosis. PLS3 may play a role in bone mineralization but the pathogenetic mechanisms are not fully understood. Careful clinical, radiological and biochemical profiling of the associated phenotypes, together with characterisation of the tissue-level pathology and the involved cellular events in these rare disorders are of great value. Such studies can lead to discoveries that will benefit not only patients with these particular disorders but may prove efficacious even in the treatment of more common skeletal disorders, such as postmenopausal osteoporosis or osteoarthrosis.

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