Unravelling the effect of an osteopetrotic Snx10 mutation on bone, muscle and other tissues

Introduction:

Osteopetrosis is a heterogeneous disease of increased bone mass and reduced bone resorption due to osteoclast malfunction. Our trilateral project, together with scientist and physicians from Israel and Palestine, aims to improve patient care and increase understanding of the cellular and molecular details of a severe autosomal recessive form of osteopetrosis caused by a R51Q point mutation in the protein SNX10.

Material and methods:

The experiments are carried out with the help of a murine Snx10 R51Q model as the structure of the protein is highly conserved between human and mouse.

Results:

Long bones in homozygous Snx10 R51Q mice are dense (Bone volume/tissue volume of 5 week old male WT siblings: WT: 5,858 ± 1,359%; Hom: 75,48 ± 9,044%) but brittle (Tissue mineral density of WT: 0,9003 ± 0,03769 CaHA g/cm3; Hom: 0,7690 ± 0,02230 CaHA g/cm3). Mutant mice also show strongly reduced osteoclast numbers (N.Oc./B.Pm (µm): WT 1,358 ± 0,3162; Hom: 0,4076 ± 0,2845) and function in vivo. Ruffled border formation and acid secretion are impaired. Interestingly also osteoblasts numbers are decreased (N.Ob./B.Pm (µm): WT: 20,56 ± 13,00; Hom: 8,281 ± 2,979). Muscles and other tissues, thought smaller in size, appear surprisingly normal.

Discussion:

The analysis of the mouse model confirms the Snx10 R51Q mutation as a cause for osteopetrosis. The bone phenotype can be rescued by autologous WT bone marrow transplantation four days after birth but tooth eruption remains a problem. We are currently investigating the molecular mechanisms of osteoclast and osteoblast impairment as well as chondrocytes in these mice in order to understand the impact of the mutation on chondral versus desmal ossification.

Key words:

Osteopetrosis, µCT, Snx10