Towards a better understanding and new therapeutics of osteopetrosis.

Lack of or dysfunction in osteoclasts result in osteopetrosis, a group of rare but often severe, genetic disorders affecting skeletal tissue. Increase in bone mass results in skeletal malformation and bone marrow failure that may be fatal. Many of the underlying defects have lately been characterized in humans and in animal models of the disease. In humans, these defects often involve mutations in genes expressing proteins involved in the acidification of the osteoclast resorption compartment, a process necessary for proper bone degradation. So far, the only cure for children with severe osteopetrosis is allogeneic hematopoietic stem cell (HSC) transplantation but without a matching donor this form of therapy is far from optimal. The characterization of the genetic defects opens up the possibility for gene replacement therapy as an alternative. Accordingly, HSC-targeted gene therapy in a mouse model of infantile malignant osteopetrosis was recently shown to correct many aspects of the disease.