Osteopetrosis: Pathogenesis, Clinical Management, and Emerging Therapies

Osteopetrosis is a heterogeneous group of bone diseases with increased bone density as a result of defective osteoclast function or differentiation. The clinical presentations range from the early, often lethal, infantile malignant forms to the mild autosomal dominant forms. This review provides recent updates in preclinical findings regarding molecular genetics, diagnosis, and novel therapeutic approaches in osteopetrosis.

The diagnosis is radiologic, supported by biochemical and genetic examination to identify mutations in the key genes involved in osteoclasts, TCIRG1, CLCN7, OSTM1, SNX10, RANK, and RANKL. Treatment is at present largely the management of complications and includes vitamin D and calcium supplements, IFN-γ therapy, and hematopoietic stem cell transplantation (HSCT), the latter being the treatment of choice for most forms of osteopetrosis. Two gene therapy- and iPSCs-derived strategies, based on reconstituting the function of osteoclasts, have been recently developed for the management of this hereditary bone disease. Furthermore, emerging findings suggest the possible involvement of epigenetic mechanisms, such as non-coding RNAs (ncRNAs), in osteopetrosis pathophysiology, paving the way for potential novel diagnostic biomarkers and tailored molecular treatments. The aim of this review is to provide an overview of recent progress in molecular genetics, diagnosis, and novel therapeutic strategies in osteopetrosis and to illustrate conceivable scenarios in regenerative and gene-based therapy.