Bone Abstracts

Osteoclasts are giant multinucleated skeletal cells of hematopoietic origin primarily responsible for bone resorption. Their functional impairment disturbs bone homeostasis and, to a variable extent, a number of other processes, such as growth, hematopoiesis and immune function. The accumulation of bone tissue owing to failure in bone resorption results in increased bone density, which is the hallmark of osteopetrosis (OP), a heterogeneous group of monogenic disorders with autosomal recessive or dominant or X-linked inheritance pattern. Depending on the affected gene, OP arises from a defect of OC resorptive function (‘OC-rich’ forms) or more rarely from an OC differentiation defect (‘OC-poor’ forms). The natural course of the disease often comprises severe complications and death during childhood. On the other hand, an increasing number of patients surviving until adulthood without a cure (hence classified as intermediate) are being reported, which raises questions regarding long-term prognosis and disease mechanisms. Over the last 20 years, the elucidation of the genetic basis of human OP has been crucial for diagnosis, prognosis and treatment and, more in general, has contributed to understand basic bone biology mechanisms. In addition, in recent years Next Generation Sequencing technologies have allowed identifying new genetic defects in single patients with peculiar phenotypes. Most of them affect genes already known to play a role in bone homeostasis (TRAF6, LRRK1, MITF, CSF1R, RELA, ITGB3); nonetheless, in some cases, the underlying pathogenic mechanism still has to be clarified. At present, about 10% of OP patients lack a molecular classification; in these cases, new, unexpected genes could be affected or known genes could harbor elusive defects. In order to fill the gap, we will need to find strategies integrating the technological power of NGS technologies and a better capacity to interpret genomic variations. In my presentation, I will review current knowledge of the molecular and cellular aspects of OP and highlight open questions for future research.

Disclosure: The authors declared no competing interests.

Abstract unavailable.