Research Interests
Delineation of osteal macrophage function in the bone
microenvironment: dual roles in bone dynamics and stem cell
niches.
Bone and joint diseases are a national and international health
and research priority costing the Australian health system over $10
billion annually. The bony skeleton is a dynamic metabolically
active tissue that is continuously remodelled and repaired to
maintain calcium homeostasis and structural integrity. The
microenvironment at the inner surface of long bones (endosteum),
including the bone matrix and associated bone lining cells, is
crucial to the dynamic processes of bone modelling and remodelling.
I have recently characterized 'osteomacs' as a resident tissue
macrophage population within bone lining tissues and have shown
that they promote bone mineralization in vitro and are necessary
for the maintenance of bone forming osteoblasts in vivo. Thus
osteomacs are cellular constituents of endosteal niches and play an
osteoblast-support function in this microenvironment. We are
investigating the unique phenotype and expression profile (mRNA and
protein) of osteomacs in order to fully delineate their functional
potential in bone dynamics.
Recently it has been shown that the endosteal environment is
also essential for the maintenance of mesenchymal stem cell (MSC)
and haematopoietic stem cell (HSC) niches. Osteoblasts need to be
present on the bone surface to ensure HSC maintenance in the
endosteal niche. Therefore we hypothesised that osteomacs, as a
consequence of their presence in the niche and osteoblast
support-function, contribute both indirectly and directly to the
generation of this stem cell nursery. We have shown that loss of
osteomacs and subsequently osteoblasts occurs during G-CSF induced
HSC mobilization. Importantly, in vivo depletion of osteomacs
(using transgenic Mafia mice) also causes marked egress of HSC from
bone marrow into the blood and spleen. These data provide
compelling support that osteomacs are required for maintenance of
osteoblast bone forming surfaces and provide caretaker support for
the endosteal stem cell niches.
My research team has a number of projects that aim to understand
the cellular architecture of the endosteal stem cell niches and the
role of osteomacs in this environment. This is an essential step
toward enhancing clinical HSC mobilization options in order to
improve bone marrow transplantation outcomes in multiple myeloma
and lymphoma and also ensuring that the promise of MSC therapy is
translated into a clinical reality.
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Research Projects
Characterising the osteomac phenotype.
Resident tissue macrophages are present in almost all tissues
and many of these populations have unique molecular profiles that
are determined by the microenvironment of the host tissue. We are
using microarray and proteomic strategies to compare osteomacs to
other tissue macrophage populations and identify their unique
molecular profile. Identification of the "osteomac" phenotype is
essential to fully understand the functional role of these cells
and will identify molecular strategies for targeting this
population for experimental and/or therapeutic purposes.
Determine how osteomac activation influences their bone and
stem cell supportive functions.
Macrophages are highly adaptable components of the immune
system. We hypothesise that the activation state/phenotype of
osteomacs will dictate their functional role in the endosteal
microenvironment. In vitro treatment of macrophages with
polarizing signals and in vivo models are being used to
investigate this hypothesis. Understanding how osteomac phenotype
alters their function in vivo will help to understand the
pathology of bone diseases.
Do osteomacs help create MSC and HSC niches?
Our preliminary data support that osteomacs are a component of
the HSC endosteal niche. Adoptive transfer techniques in
conjunction with in situ staining approaches are being
used to characterise the in vivo associations of osteomacs
with MSC and HSC and precisely where these stem cell niches are
located. Additionally, an in vivo mobilization model is
being used to investigate osteomac regulation of stem cell egress
from these niches. Finally, cell culture systems are being used to
determine whether osteomacs influence the fate of HSC and MSC in
terms of their terminal differentiation into osteoclast and
osteoblast cells respectively. This research will describe and
entirely new functional role for macrophages in stem cell
homeostasis and have broad implications for stem cell
based-therapies.
PhD Projects available
- Macrophage regulation of the hematopoietic stem cell niche
- A novel osteoimmunological approach to identify anabolic bone
therapies for osteoporosis & fracture repair
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Key publications
Raggatt LJ*, Chang MK*, Alexander KA, Kuliwaba
JS, Fazzalari NL, Schroder K, Maylin ER, Ripoll VM, Hume DA and
Pettit AR. Osteal tissue macrophages are intercalated throughout
human and mouse bone lining tissues and regulate osteoblast
function in vitro and in vivo. Journal of Immunology, 2008,
15;181(2):1232-44. (IF: 6.1/Citations 3; May 05; *authors
contributed equally to this work).
Raggatt LJ, Qin L, Tamasi J, Jefcoat Jr SC,
Liew FY, Beverlock L, Feyen JHM and Partridge NC. IL-18 is
regulated by parathyroid hormone and is required for its bone
anabolic actions. Journal of Biological Chemistry (2008) 283(11):
6790-8. (IF: 6.5/Citations 1; May 05)
Reviews
Pettit AR, Hume DA and Raggatt LJ.
Osteal Macrophages: A new twist on coupling during bone dynamics.
Bone 2008, 15;181(2):1232-44. (IF: 6.2 / Citations 1; May 05)
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