Bone Abstracts

Homozygous or compound heterozygous mutations in the RECQL4 helicase gene are responsible for 65% cases of Rothmund-Thomson syndrome (RTS-type II), a rare premature ageing syndrome. RTS-II patients exhibit poikiloderma and various kinds of bone abnormalities: short stature, congenital radial ray anomalies, bone microarchitecture defects, diffuse or localized osteoporosis and increased risk of osteosarcoma. Mutations in the RECQL4 gene are also responsible for two other rare diseases, RAPADILINO and Baller-Gerod syndromes. These three syndromes are associated with specific clinical signs but have in common skeletal abnormalities, suggesting that the RECQL4 protein may play a key role in the development and maintenance of bone tissue. RECQL4 belongs to the highly conserved RECQ helicase that play significant roles in DNA metabolic processes and maintenance of genome stability. However, the function of RECQL4 and the cellular pathways in which it is involved remains poorly understood.

The aim of our work is to get a better understanding of the pathophysiology of Rothmund-Thomson syndrome by exploring the role of the RECQL4 helicase in bone biology. Our data suggest that RECQL4 is involved in signaling pathways important for osteoclastogenesis. We found that RECQL4 expression is transiently up-regulated by RANKL during osteoclast differentiation of RAW264.7. We next observed that overexpression of RECQL4 in the RAW264.7 causes osteoclast differentiation even in the absence of RANKL. Osteoclasts overexpressing RECQL4 exhibit increased bone resorption, modified cytoskeleton and accelerated apoptosis compared to control cells. Q-PCR analyses revealed that RECQL4 is able to induce NFATc1, a key transcription factor of osteoclast differentiation. Taken together these data suggest that RECQL4 may be a regulator of osteoclastogenesis. Molecular mechanisms underlying this unexpected function of RECQL4 are under investigation and will be discussed.