Project VI

Mechanisms/molecules essential in sealing zone and ruffled border formation, focus on autophagy and transcytosis.

Anh Tran

My name is Anh Tran and I am the early stage researcher of project VI. I am originally from Perth, Australia where I studied at the University of Western Australia (UWA) and graduated with a bachelor of science (majors in pathology, anatomy and human biology). I also undertook an honours project with the UWA Centre for Orthopaedic Research where I explored the transcytotic route of degraded bone matrix in resorbing osteoclasts using immunofluorescence confocal microscopy and time-lapse confocal microscopy (live cell imaging). I saw for the first time how osteoclasts remove bits of bone matrix in real time, a real EUREKA moment!

Doing this work as part of my degree really sparked my interest in the unique osteoclast and led me to pursue research abroad with the Musculoskeletal Programme at the University of Aberdeen. You can reach me by email on anh.tran@abdn.ac.uk

Fraser Coxon

I am Fraser Coxon, the primary supervisor of project VI and second supervisor of project VIII. I have worked on osteoclasts at the University of Aberdeen for 15 years, initially in elucidating the molecular mechanism of action of bisphosphonates. These drugs are powerful inhibitors of bone resorption by osteoclasts and as a result have become the most widely used treatments for bone diseases such as osteoporosis.

My research in this area revealed the crucial role of intracellular trafficking pathways for degradation of bone by osteoclasts, which has led to my current focus on understanding the molecular mechanisms that control these pathways in osteoclasts in health and disease.

When not in the lab I enjoy spending time with my family, playing and watching sport (in particular soccer and tennis), and exploring the Scottish countryside with my camera. I can be contacted by email on f.p.coxon@abdn.ac.uk.

Miep Helfrich

I am Miep Helfrich (officially Marie Helfrich) and originally from Groningen in The Netherlands. For the past 26 years I have lived in the UK, the last 22 years in Aberdeen in Scotland.

I have studied osteoclasts since my PhD at the University of Leiden, in The Netherlands. They are the most fascinating cells I can think of: bulldozers that squirt acid and degrading enzymes ahead of them, but at the same time can look like beautiful jellyfish dancing over the bone surface. I have studied osteoclasts in health and in diseases such as osteopetrosis and Paget’s disease of bone where they do not work at all, or work too hard respectively. From such studies in disease we learn a lot about how the cells do their work normally. I use mainly microscopical techniques and have a particular fondness of ultrastructural microscopy.

I am excited that for the coming 4 years I will be working so closely with other osteoclast enthusiasts to train up a new generation of osteoclastophiles. I am the first supervisor on Emma’s project and second supervisor of the project of Anh.

When I am not in the lab I love being out in the Scottish hills and collecting bones, antlers and other materials for craft projects. I also love art and visiting museums, exhibitions and performances. Combining art and science is something I would love to do as part of the Euroclast public engagement activities. You can contact me at m.helfrich@abdn.ac.uk


Our Project

Osteoclasts resorb bone via a specialised bone-resorbing membrane domain called the ruffled border (RB), which is formed through the trafficking and fusion of secretory lysosomes containing osteolytic enzymes. Following the degradation of bone matrix, the RB also facilitates the uptake of the degraded products, which are trafficked in vesicles through the cell via transcytosis.

This project aims to determine the molecular mechanisms controlling these processes, with a particular focus on autophagy. Autophagy is a vesicular trafficking process whereby damaged cellular components become incorporated into autophagosomes, where they are degraded and recycled following fusion with lysosomes. LC3 is an autophagosome-associated protein widely used as a marker of autophagy; this protein is important for both recruitment of the cargo to be degraded and fusion with lysosomes. LC3 has recently also been associated with non-autophagic processes such as phagocytosis in macrophages, through promoting fusion of phagosomes with lysosomes.

In osteoclasts, LC3 and autophagy have been linked to both RB formation and transcytosis of degraded bone matrix, although the precise relationship and mechanisms involved remain unclear. We will elucidate this using a combination of advanced microscopic approaches and novel mouse models, including transgenic mice expressing fluorescent LC3 conjugates.

To examine the formation of the RB and transcytosis of bone matrix, osteoclasts cultured on bone in vitro will be analysed by 3D confocal and 4D live cell imaging. The use of transgenic mouse models deficient in autophagy, as well as autophagy-modulating agents, will help to reveal the contribution of this process to RB formation, transcytosis and bone resorption by osteoclasts.

Our postal address is:
Musculoskeletal Research Programme
Institute of Medical Sciences
Foresterhill
Aberdeen
AB25 2ZD
UK

Here we are on the Foresterhill Campus in Aberdeen: Miep, Anh and Fraser