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Molecular and phenotypic characterisation of human pre-osteoarthritic chondrocytes from post-traumatic joints

Applicant Pelttari Karoliina
Number 151396
Funding scheme Marie Heim-Voegtlin grants
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cellular Biology, Cytology
Start/End 01.02.2014 - 30.04.2016
Approved amount 220'742.00
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Keywords (4)

Early osteoarthritis; Cartilage tissue engineering; Regenerative medicine; Nasal chondrocytes

Lay Summary (German)

Lead
Unbehandelte traumatische Knorpelverletzungen erhöhen die Wahrscheinlichkeit der Entstehung von Osteoarthrose (OA) und werden daher mit zell-basierten Techniken repariert, z.B. mit (Matrix-assoziierter) autologer Chondrozytentransplantation (MACT/ACT) oder Microfracture. Bei einigen Patienten aber versagen diese Reparaturmethoden.
Lay summary
Es wird angenommen, dass ein Trauma strukturelle Veränderungen im Gelenk bewirkt, die zur Entstehung von OA beitragen. Diese (prä-) osteoarthrotische Micro-Umgebung hat sowohl Einfluss auf den Phänotyp der ansässigen Knorpelzellen in der direkten Umgebung des ursprünglichen Traumas („erkrankter Knorpel“), als auch auf die Reparaturkapazität rekrutierter oder transplantierter Zellen.

Diese Studie untersucht, ob Knorpelzellen aus „erkranktem Knorpel“ sich von Zellen aus „gesundem Knorpel“ unterscheiden und womöglich einen Phänotyp ähnlich osteoarthrotischer Knorpelzellen aufweisen. Hierfür werden diese Zelltypen bezüglich Proliferationsrate und Knorpelbildungspotential (in vitro und in vivo) miteinander verglichen. Desweiteren soll der Einfluss des erkrankten Knorpels auf die Knorpelbildungsfähigkeit von mesenchymalen Stammzellen und artikulären Knorpelzellen (repräsentativ für die bei Microfrature und ACT eingesetzten Zellen) aber auch von nasalen Knorpelzellen (als alternative Zellkomponente für ACT) untersucht werden. Hierfür wird erkranktes Knorpelgewebe mit den zuvor erwähnten Zelltypen co-kultiviert und dabei deren Differenzierungspotential zu Knorpelgewebe dokumentiert. Faktoren, die vom erkrankten Knorpel produziert werden und potentiell die Knorpelbildungsfähigkeit beeinträchtigen, werden unter Zuhilfenahme von Multiplexed Protein Detections Arrays identifiziert.

Im Rahmen dieses Forschungsprojektes sollen wichtige Informationen zum Verständnis der biologischen Prozesse im Gelenk in Folge einer Verletzung erarbeitet werden und dadurch die bisher unzureichend beschriebene Entwicklung der post-traumatischen frühen OA besser verstanden werden. Das Verständnis der Beziehung von strukturellen Veränderungen im beschädigten artikulärem Knorpel und der fortschreiten Entwicklung in Richtung einer darauffolgenden OA wird hilfreich sein, die Qualität der Knorpelreparatur und damit verbunden die Lebensqualität des Patienten zu verbessern.

Direct link to Lay Summary Last update: 15.01.2014

Responsible applicant and co-applicants

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Publications

Publication
A potential role of homeobox transcription factors in osteoarthritis
Pelttari Karoliina, Barbero Andrea, Martin Ivan (2015), A potential role of homeobox transcription factors in osteoarthritis, in Annals of Translational Medicine, 3(17), 254.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Knee Osteoarthritis Symposium Poster Molecular and phenotypic characterization of human chondrocytes from post-traumatic joints 18.06.2015 Lausanne, Switzerland Pelttari Karoliina;


Abstract

Background: Untreated traumatic injuries of the articular cartilage highly increase the possibility of the patient to develop post-traumatic osteoarthritis (OA). Therefore significant cartilage lesions are commonly treated by cell-based cartilage repair procedures, such as (matrix assisted-/) autologous chondrocyte transplantation (MACT or ACT) or micro-fracture. Still, for some of the patients these established techniques fail to regenerate the damaged cartilage tissue. Recent experimental evidences suggest that structural changes induced by the original trauma induce changes in the joint that contribute to the evolution of OA. This (pre-)osteoarthritic microenvironment is likely to influence the phenotype of the resident chondrocytes at the proximity of the primary defect site (which will be referred to as “diseased cartilage” in the following), as well as the repair capacity of the recruited or transplanted cells. This study generally evaluates whether structural changes occurring in traumatic joint microenvironments influence the properties of resident chondrocytes and/or modulate the cartilage forming capacity of recruited or transplanted chondrogenic cells in the defect.Working hypothesis: The 1st working hypothesis of this project proposal is that diseased chondrocytes display features of OA chondrocytes and have a lower chondrogenic differentiation capacity as compared to healthy chondrocytes. I furthermore hypothesise that the diseased cartilage surrounding the primary cartilage defect impairs the cartilage formation capacity of healthy articular chondrocytes and MSC (mesenchymal stromal cells), but is less detrimental to the chondrogenic properties of nasal chondrocytes (NC) (i.e. cells with a higher plasticity and cartilage forming capacity as compared to AC).Specific aims: Aim 1 of this project investigates whether “diseased” articular chondrocytes (dAC) have an altered phenotype similar to osteoarthritic articular chondrocytes (oaAC). Therefore the proliferation rate, chondrogenic differentiation capacity (in vitro and in vivo), and the expression of inflammatoty and angiogenic factors will be determined for dAC and compared to healthy articular chondrocytes (hAC) (harvested from a macroscopically unaffected region of the same joint) as well as oaAC (serving as control). Proliferation rate and cartilage forming capacity will additionally be assessed for single-cell derived clonal dAC subpopulation. Aim 2 will assess the effect of a “diseased microenvironment” in the joint on the cartilage forming capacity of MSC and expanded AC (representing the therapeutically applied cells) as well as NC (as a potential alternative cell source for ACI). Therefore “diseased” cartilage tissue will be co-cultured with the aforementioned cells in a trans-well system to determine the chondrogenic differentiation capacity of MSC, AC and NC in a “diseased” environment. Potential factors released by the “diseased cartilage” that modulate the cartilage forming capacity of chondrogenic cells will be identified with the help of a Multiplexed Protein Detection Array and their functionality verified by blocking with specific antibodies.Expected value of the proposed project: The here described set of proposed experiments will acquire crucial information about the biological processes involved in the joint after injury and thus of the development of post traumatic early OA, a phenomenon that remains not well described to date. Furthermore, understanding the relationship of structural changes in a damaged articular joint and its progress towards subsequent OA will help to improve the quality of cartilage repair and consequently the quality of life for patients - perhaps eventually leading to the development of new treatment strategies, e.g. the usage of alternative cell sources, such as NC for the repair of pre-osteoarthritic cartilage lesions.
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