Towards a better understanding and new therapeutics of osteopetrosis

Abstract

Summary 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.

Nonablative neonatal bone marrow transplantation rapidly reverses severe murine osteopetrosis despite low-level engraftment and lack of selective expansion of the osteoclastic lineage

“…6A, B). From this we can calculate the probability that osteoclasts formed will not be GFP-marked to be (1-0.04) (8) which is 72%; thus the remaining 28% of the multinucleated cells should be positive for GFP, corroborating our observed percentage of GFP þ osteoclasts. This is concordant with the findings of Coccia and colleagues, who after transplantation of a 5-month-old girl with IMO with bone marrow from her brother used fluorescent in situ hybridization (FISH) for the Y-chromosome to study donor chimerism and found that 30% of mononuclear cells in the blood were of male origin, whereas 81% of the osteoclasts contained at least one Y-positive nucleus.…”

“…(7) Infantile malignant osteopetrosis (IMO) is a severe congenital disease where development of gene therapy as an alternative therapy also is warranted. (8) The affected children have dysfunctional osteoclasts owing to a mutation in the TCIRG1 gene encoding a subunit of a V-ATPase proton pump required for bone resorption, and they suffer from skeletal abnormalities and blindness owing to optic nerve compression and face an early death if SCT cannot be performed. (9,10) Previously, it has been shown that the severe oc/oc mouse model of IMO, which also has a deletion in the Tcirg1 gene, can be rescued by transplantation in utero (11,12) or by neonatal transplantation of normal bone marrow (BM) or genetically modified oc/oc fetal liver cells after conditioning with irradiation or busulfan.…”

Regulation of bone mass and osteoclast function depend on the F-actin modulator SWAP-70

“…These models can be classified into three subgroups with respect to the underlying osteoclast pathology: differentiation defects, fusion and polarization defects, and functional defects, as reviewed by Tolar and colleagues (6) and Askmyr and colleagues. (7) Only a few of these in vivo models address the organization of the ORIGINAL ARTICLE J JBMR osteoclast cytoskeleton or specifically the formation of actin rings, or the role of RhoGTPases in osteoclast biology. (8)(9)(10)(11)(12) SWAP-70 carries an unusual arrangement of protein domains and motifs.…”

A Fatal Case of Infantile Malignant Osteopetrosis Complicated by Pulmonary Arterial Hypertension after Hematopoietic Stem Cell Transplantation

“…However, autosomal recessive form, also termed infantile malignant osteopetrosis (IMO), is usually diagnosed soon after birth with severe symptoms, including pancytopenia caused by bone marrow failure, hepatosplenomegaly, or macrocephaly with early closing of the fontanel. Mutations in at least 10 genes have been identified as causative in humans, accounting for more than 70% of all IMO cases (Askmyr et al 2008). We had reported one of these mutations previously (Michigami et al 2002).…”

“…Osteopetrosis is caused by the failure of osteoclast development or function (Askmyr et al 2008). The overall incidence of osteopetrosis is about 1 : 20,000.…”