Bone Abstracts

Recent GWAS have identified variants in the OPTN gene that predispose to Paget’s disease of Bone (PDB), a disease characterised by focal areas of increased bone turnover and enhanced osteoclast activity, suggesting a role for this gene in bone metabolism. The aim of this study was to investigate the role of OPTN in bone metabolism using a mouse model (Optn^D477N/D477N) which harbours a D477N point mutation in the polyubiquitin binding domain of the Optn gene.

The skeletal phenotype of four-month Optn mutant (n=8) and matched wild type (WT; n=8) animals was assessed using bone histomorphometry, micro CT, and in vitro osteoclast culture assays. Histomorphometric analysis of bone sections showed evidence of increased bone turnover in Optn mutant mice. Bone resorption parameters were higher in Optn mutant mice compared to WT animals (Osteoclast Number/Bone Surface; 8.6±2.0 vs 6.0±1.3; P<0.001; and Osteoclast Surface/Bone Surface; 18.0±5.8 vs 11.8±3.8; P<0.001). Bone formation parameters were also higher in mutant mice compared to WT (Osteoid Surface/Bone Surface; 9.6±4.7 vs 5.0±3.1; P=0.001 and Osteoid Volume/Bone Volume 1.2±0.6 vs 0.6±0.5; P=0.007). Micro CT analysis revealed no significant differences in bone morphology between WT and mutant mice.

In agreement with the in vivo data, multinucleated osteoclasts (>3 nuclei) formed from mutant bone marrow cells were significantly higher (239±17) than those formed from WT (195±22; P<0.001) in vitro. Additionally the number of large osteoclasts (>10 nuclei) was significantly higher in mutant (37±5) compared to WT (15±5; P<0.001) cells.

In conclusion, we have shown for the first time that OPTN plays a role in regulating bone turnover and our data suggest a direct effect of OPTN on osteoclast formation. This may partly explain optineurin’s role in PDB susceptibility but further studies will be required to define the mechanism by which optineurin regulate bone metabolism.