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Understanding bone mass using collageneases and aggrecanases


Project Description

Bone is not only essential for locomotion, support and protection but crucial for many aspects of animal and human health. Specifically, bone is a calcium/phosphorous reservoir, is integral to glucose metabolism, houses the hematopoietic system and cross-talks with renal and reproductive systems. Ossification of the entire post-cranial, endochondral skeleton throughout ontogeny, growth and evolution relies entirely on an ECM secreted by chondrocytes. A distinctive osteoblast cell type that shapes and maintains skeletal physiology achieves bone formation upon this cartilage ECM template.

We generated a mouse with severely modified growth plate cartilage ECM remodeling. We targeted Tissue Inhibitor of MetalloProteinase-3 (TIMP3), a member of the metzincin family of MMP inhibitors that inhibits a wide spectrum of ECM-modifying enzymes including aggrecanases, collagenases and sheddases. overexpressing TIMP3 specifically in chondrocytes, via a collagen type II promoter/enhancer (TIMP3 Tg;) reveal: i) transient long bone shortening that is restored before adulthood; ii) diminished trabecular and cortical bone mass, with defective architecture and lower fracture resistance at all ages, iii) restriction of TIMP3 Tg impact to only endochondral bones and crucially, iv) deficiencies in osteoblast proliferation and differentiation that persists in vitro. Along with TIMP3 transgene concentration-dependence. Our data show that bone formation relies at least partly on the cartilage ECM encountered during osteoblast recruitment. The changes in the growth plate that underpin these divergent phenotypes are however unknown.
We aim is to define changes in growth plate chondrocyte development by characterising transcriptional and ECM proteome/degradome signatures.
2. to determine the transcriptional, proteomic and epigenetic regulators of osteoblast behaviour controlled by modified cartilage ECM.

The student will learn a number of techniques during the course of this PhD ranging from cell culture to transfection and molecular biology to generate vectors to express specifically in chondrocytes. The major task will be using bioinformatics to understand transcriptome and proteome signature in transgenic mice cartilage. The student will have a chance to engage in vivo models of osteoarthritis and osteoperosis and test the effect of ECM remodeling in such models.

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasise the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

To apply please send your CV and a covering letter to .
This position will close once a suitable candidate is found.

Funding Notes

This is a self-funded opportunity.

References

1: Kanakis I, Liu K, Poulet B, Javaheri B, van 't Hof RJ, Pitsillides AA, Bou-Gharios G. Targeted inhibition of aggrecanases prevents articular cartilage degradation and augments bone mass in the STR/Ort spontaneous model of osteoarthritis. Arthritis Rheumatol. 2018 Oct 31.
2: Javaheri B, Caetano-Silva SP, Kanakis I, Bou-Gharios G, Pitsillides AA. The Chondro-Osseous Continuum: Is It Possible to Unlock the Potential Assigned Within? Front Bioeng Biotechnol. 2018 Mar 21;6:28.
3: Miller B, Spevak L, Lukashova L, Javaheri B, Pitsillides AA, Boskey A, Bou-Gharios G, Carriero A. Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice. Calcif Tissue Int. 2017Jun;100(6):631-640.
4: Poulet B, Liu K, Plumb D, Vo P, Shah M, Staines K, Sampson A, Nakamura H, Nagase H, Carriero A, Shefelbine S, Pitsillides AA, Bou-Gharios G. Overexpression of TIMP-3 in Chondrocytes Produces Transient Reduction in Growth Plate Length but Permanently Reduces Adult Bone Quality and Quantity. PLoS One. 2016 Dec 21;11(12):e0167971.
5.Gardiner MD, Vincent TL, Driscoll C, Burleigh A, Bou-Gharios G, Saklatvala J, Nagase H, Chanalaris A. Transcriptional analysis of micro-dissected articular cartilage in post-traumatic murine osteoarthritis. Osteoarthritis Cartilage. 2015 Apr;23(4):616-28.

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