Role of stromal-vascular communication and remodeling in anabolic osteoporosis therapy

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This is one of two research projects studying anabolic treatments for osteoporosis. KU Leuven is the home institution for this project. To view the Melbourne-based partner project, click here.

With ageing our bones become brittle and prone to fractures, known as osteoporosis. Despite widespread use of therapies blocking bone loss, osteoporosis represents a major public health concern. There is a large clinical need for bone-building (osteo-anabolic) treatments that sustainably improve bone mass in patients. Intermittent parathyroid hormone (iPTH), the first-approved osteo-anabolic drug, effectively stimulates bone formation, but suspected side-effects unfortunately limit its use. Understanding the mechanisms of action of iPTH at the cellular-molecular levels could identify strategies for improved therapeutic use of this powerful drug or for developing safer new treatments. Two major angiogenic pathways (VEGF and PDGF signalling) have been identified as vital for bone formation during growth and fracture repair, along with MMP-9, a proteolytic and pro-angiogenic molecule. These pathways can jointly mediate activation and expansion of skeletal stem/progenitor cells and blood vessels, both needed for bone formation. Could this stromal-endothelial communication and vascular remodelling also be important for therapeutic bone gain? This question will be tackled here. The investigation will focus on whether VEGF, PDGF and MMP-9 are functionally involved in iPTH-induced bone formation and required for the therapeutic outcome.

Project goals

This work can lead to improved or new anabolic treatment approaches for osteoporosis, based on manipulation of the stromal-vascular bone unit. The aim is to determine whether remodelling of the stromal-vascular components of the bone marrow and in cortical bone are required for the bone forming effects of iPTH treatment. Moreover, the aim is to to unravel the cellular and molecular mechanisms that mediate SSPC-endothelial cell crosstalk induced by iPTH, and how they contribute to vascular adaptations, SSPC activation, and the osteo-anabolic outcome of iPTH treatment. This will determine whether VEGF and PDGFR signalling and MMP-9 activity are required for iPTHinduced bone formation.

The specific aims are:

  1. Define if SSPC-derived VEGF mediates the vascular changes and bone anabolic effect induced by iPTH
  1. Assess whether SSPC activation and PDGFR signalilng in SSPCs drives osteoblastogenesis and bone formation in response to iPTH.
  1. Identify whether MMP-9 is required for the angiogenic and osteo-anabolic effects of iPTH.

Supervision team

The University of Melbourne – Prof Natalie Sims

KU Leuven – A/Prof Christa Maes

Click on the researcher's name above to learn more about their publication and grant successes.

Who we are looking for

We are seeking a PhD candidate with the following skills:

  • Demonstrated experience in the field of medicine/physiology
  • Demonstrated experience with scientific computation
  • Demonstrated ability to work independently and as part of a team
  • Demonstrated time and project management skillsDemonstrated ability to write research reports or other publications to a publishable standard (even if not published to date)
  • Excellent written and oral communication skills
  • Demonstrated organisational skills, time management and ability to work to priorities
  • Demonstrated problem-solving abilities.

Further details

  • The PhD candidate will benefit from the combined expertise of the project supervisors, and the embedding into two research environments.
  • The collaboration between A/Prof Christa Maes and Prof Natalie Sims is designed to build a strong network of researchers interested in the cross-tissue communication that exists within the skeleton, and between the skeleton and other organ systems in the body. Future research work will make use of the resources developed in these projects (such as RNAseq data on samples collected, additional tissue samples from the murine studies, communication pathways identified) to fully characterise the interactions between the vasculature and bone formation in both marrow and trabecular contexts in models of skeletal disease and disrepair, including age-related bone loss, fracture healing, multiple myeloma, breast cancer metastases, and chronic kidney disease. All of these have well-established murine models that will be interrogated with our combined technical expertise, shared and duplicated across the two institutions. In addition, Prof Natalie Sims is a world-renowned expert in PTH, and will contribute her highly specialised methodologies for cortical bone analysis to extend the study to this important part of the bone: the outer shell that provides most of the bone’s strength.
  • This PhD project will be based at KU Leuven with a minimum 12-month stay at the University of Melbourne.
  • The candidate will be enrolled in the PhD program at the Department of Development and Regeneration at KU Leuven, and in the PhD program at the St Vincent's Hospital/University of Melbourne.

To apply for this joint PhD opportunity, and to view the entry requirements, visit How to apply.

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