Bone Abstracts

The Rab family GTPases Rab27a and Rab27b play an important role in the trafficking of lysosome-related organelles in specialised cells, such as melanocytes. Since secretory lysosomes, also considered a lysosome-related organelle, are important for osteoclast and osteoblast function, we hypothesised that Rab27 plays a role in bone physiology. In support of this, a recent study demonstrated impaired transport of RANK ligand to the plasma membrane in osteoblasts from mice lacking the Rab27 effector Munc13-4. To assess the potential role of Rab27 in bone cells, we analysed the bone phenotype of mice lacking Rab27a and Rab27b (Rab27^ash/ash Rab27b^−/−; DKO). MicroCT analysis of 8-week-old DKO mice revealed 25% lower bone volume than WT mice. This is likely due to impaired osteoblast function, since Rab27a was detected in mouse calvarial osteoblasts, and increased during differentiation, whereas expression of Rab27a markedly decreased during osteoclast differentiation. Rab27b could not be detected in either cell type, suggesting that Rab27a, but not Rab27b, is important for osteoblast function. Surprisingly, overexpressed GFP-Rab27a localised mainly to the Golgi apparatus rather than lysosomes in osteoblasts. Nevertheless, in support of a role for Rab27 in osteoblasts, mineralisation by differentiated DKO osteoblasts in vitro was slightly reduced compared to WT osteoblasts, whereas there were no differences in the formation or activity of osteoclasts generated from WT or DKO mice. However, the formation of osteoclasts in co-cultures of bone marrow cells with osteoblasts from DKO mice was not impaired, indicating normal RANK ligand trafficking in osteoblasts lacking Rab27. These data therefore suggest that Rab27a is important for bone formation by osteoblasts, but not for stimulation of osteoclastogenesis, where other Rabs, that also use Munc13-4 as an effector, may be involved.