Osteopetrosis: from Animal Models to Human Conditions

Abstract

The term ''osteopetrosis'' is applied to a group of disorders characterized by an increased bone density, due to an inadequate bone resorption. A considerable part of our current knowledge on osteoclast biology is based on the study of osteopetrotic animal models. The search for mutations in these animals has unveiled many molecular mechanisms underlying osteoclast differentiation and functioning. It also supplied new candidate genes for the identification of genes involved in the human variants of this disease. All osteopetrotic genes identified so far in humans have their animal counterpart. The reverse is not true. This can partially be explained by the fact that still more than 30% of all patients suffer from osteopetrosis with an unkown molecular defect. Therefore, the studies of the osteopetrotic animal models and the correlating human osteopetrotic forms were and are still very important for our knowledge of the aetiology, prognosis and treatment of this disease. This review focuses on osteopetrotic animal models as well as human osteopetrotic conditions and their impact on osteoclast biology, pathogenesis and treatment.

Multiomics landscape of the autosomal dominant osteopetrosis type II disease-specific induced pluripotent stem cells

“…However, there is no curative therapeutics for ADO2 [ 4 ]. In most patients, they result from heterozygous mutations in CLCN7, which can result in nerve compression syndrome, visual loss and bone marrow failure, and may be presented diverse clinical and radiological manifestations ranging from asymptomatic or relatively mild symptoms to the very severe phenotype [ 2 , 5 ]. Notably, some promising results suggest that small interfering RNA (siRNA)-based therapeutics may be used to cure patients with ADO2 and have been further demonstrated to be feasible in osteoporotic animal models [ 6 , 7 ].…”

“…A recent transcriptomic study has been suggested that changes in the expression of ITGB5, PRF1, WARS, and SERPINE2 may be part of the osteoclast phenotype, in addition to the acidification dysfunction caused by heterozygous mutations in the CLCN7 gene in osteoclasts in ADO2 patients [ 13 ]. In the past, knowledge about the molecular characterization and pathogenesis of osteopetrosis was primarily acquired by osteoporotic animal models [ 5 , 16 – 19 ]. Recently, osteoporotic iPSC models were successfully generated from an ADO2 patient and three autosomal recessive osteopetrosis (ARO) patients, which has provided an unprecedented opportunity for the study of ADO2 pathophysiology and therapeutic application [ 1 , 20 , 21 ].…”