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Osteoarthritis (OA) is the most common form of arthritis and an
age-related, degenerative joint disease that affects more than 10%
of Canadian adults. There is no cure for this debilitating disease.
Current therapies are only partly successful and are limited to
lessening the symptoms of OA. The problem is that the specific
biological factors underlying its genesis are poorly understood,
which limits the development of effective disease modifying
therapies. However, a study published in the American Journal of
Pathology by a team led by the CRCHUM’s Dr. Mohit Kapoor has
pinpointed a key biological factor involved in the development of
OA.
Osteoarthritis occurs when cartilage, the material covering and
protecting the ends of bones, begins to erode and ultimately leads
to pain, swelling and bone-on bone movement in the affected joint.
Kapoor’s findings with laboratory animals show for the first
time that PPARγ (peroxisome proliferator-activated receptor
gamma), a nuclear receptor, plays a critical role in the expression
of the genes that regulate cartilage growth and repair. “In
its absence” explains Dr. Kapoor, “all the animals in
our study developed accelerated spontaneous
osteoarthritis.”
Although few if any human beings are born with a complete
PPARγ deficiency, as we grow older there is an almost
unavoidable gradual decline in the amount of PPARγ produced
by our bodies. Moreover, this decline can be amplified by injuries.
In concrete terms, this deficiency translates into a lessened
capacity for cartilage repair and health. For many people, the end
result is varying degrees of osteoarthritis, ranging in its effects
from occasional pain to chronic suffering and even the need for
replacement of the affected joints.
“These results are quite exciting because they open the door
to cellular therapies focussed on stimulating the production of
PPARγ in OA patients,” notes Dr. Kapoor.”
Indeed, the next step in his research is to identify key cellular
processes modulated by PPARγ.
He and his colleagues, senior scientist Dr. Yue Zhang and PhD
candidate Faezeh Vasheghani, have discovered that PPARγ is a
key mediator involved in the regulation of a cell survival/cell
death mechanism called autophagy, which also seems to be a
protective mechanism in the articular cartilage. Its dysregulation
leads to accelerated loss/death of specialized cartilage cells
called chondrocytes, which are responsible for maintaining the
integrity of the cartilage. PPARγ appears to control normal
regulation of autophagy, and any loss of PPARγ leads to its
dysregulation, to excessive cell death and eventually to severe
OA.
Using genetically modified mice and human cartilage and cells
obtained from osteoarthritic patients, Dr. Kapoor’s team
seeks to comprehensively define the role of PPARγ in the
modulation of autophagy in the cartilage. “Our hope is that
this approach will lead to several new therapies aimed at stopping
or delaying the disease itself and not merely its symptoms. In this
way effective and long-lasting relief from its symptoms will become
possible” explains
Kapoor.
About the study
“Adult cartilage-specific peroxisome proliferator-activated
receptor gamma
knockout mice exhibit the spontaneous osteoarthritis
phenotype,” was published on
January 29 in the online version of the American Journal of
Pathology http://www.ncbi.nlm.nih.gov/pubmed/23375622
About Dr. Mohit Kapoor
Dr. Kapoor is a researcher in the CRCHUM’s Musculoskeletal
research theme. He is also an assistant professor with the
Department of Medicine at the University of Montreal and an
accredited faculty member in the Department of Pharmacology at the
University of Montreal. He is also a Canadian Arthritis Network
Investigator and a Canadian Scleroderma Research Group
Investigator. His research is funded by the Canadian Institutes of
Health Research, the Institute of Musculoskeletal Health and
Arthritis, the Canada Foundation for Innovation, the Canadian
Arthritis Network, the Fonds de recherche du Québec –
Santé and Pfizer Canada. Dr. Kapoor is a recipient of The
European Society for Clinical and Economic Aspects of Osteoporosis
and Osteoarthritis Young Investigator Award and Scholarship from
the Japan College of Rheumatology.
Information
Richard Ashby
Associate Director, Information and Development
CHUM Research Centre
(514) 890-8000, ext. 14090
richard.ashby.chum@ssss.gouv.qc.ca
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