Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2016) 5 P195 | DOI: 10.1530/boneabs.5.P195

1University of Aberdeen, Aberdeen, UK; 2University of Dundee, Dundee, UK; 3University of Massachusetts, Worcester, USA; 4St Jude Children’s Research Hospital, Memphis, USA.


The autophagy protein LC3 is necessary for bone resorption by osteoclasts, although it has been suggested that this may be through a novel, autophagy-independent process, by promoting lysosomal fusion at the ruffled border (RB). This process would be analogous to LC3-associated phagocytosis (LAP), in which LC3 is acquired by phagosomes through an autophagy-independent process, and controls phagosome maturation by promoting fusion with lysosomes. We have investigated this possibility by using novel mouse models for monitoring LC3 localisation and a model in which autophagy is selectively ablated. In vitro, LC3 localises to the RB in 30% of actively resorbing osteoclasts. Most of these osteoclasts are at an early stage of RB formation; LC3 did not localise to the RB in osteoclasts associated with extensive resorption pits. We further investigated this by using an autophagy-deficient mouse model in which FIP200 is deleted in the myeloid lineage; FIP200 is essential for autophagy, but is not required for LAP. FIP200 null osteoclasts were able to target LC3 to the RB and resorb dentine despite impaired autophagy, indicating that a process similar to LAP, rather than autophagy, controls RB formation. The Rab7 effector Plekhm1 may also be involved in this process; mutations in Plekhm1 cause osteopetrosis, due to the failure of osteoclasts to form RBs and resorb bone. Furthermore, Plekhm1 binds to LC3 and plays a role in autophagosome-lysosome fusion by bridging the membranes of these two vesicle types. Surprisingly, we found little difference in autophagy in osteoclasts derived from patients with Plekhm1 mutations or in mice lacking Plekhm1, compared to family or littermate controls, respectively. By contrast, Plekhm1-deficient osteoclasts exhibited defective RBs and profoundly impaired resorptive activity. These data suggest that Plekhm1 may play a redundant role in autophagy in osteoclasts, but is essential for lysosomal fusion at the RB through interactions with LC3.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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