Project

cartilage repair; tissue engineering; osteoarthritis

Lead
Nasale Chondrozyten für die Behandlung articulärer osteoarthritischer Läsionen
Lay summary
Osteoarthrose (OA) ist die am weitesten verbreitete muskuloskeletale Erkrankung im Menschen. Sie geht mit Schmerz und  Verlust der Beweglichkeit einher und führt so zur Verminderung der Lebensqualität. Nasale Chondrozyten (NC) könnten eine attraktive alternative Zellquelle bei der Reparatur von OA-Knorpel darstellen, da sie aus einem „gesunden“ heterotrophen  Gewebe entnommen werden. Ziel dieser Studie ist die Eignung von NC in der Wiederherstellung des OA geschädigten Knorpels zu untersuchen. Wir nehmen an, dass NC mit einer OA Gelenksumgebung kompatibel sind. Diese ist definiert als die Fähigkeit der NC (i) in Anwesenheit von biochemischen/-mechanischen Signalen, die die OA Gelenksumgebung simulieren, stabilen Knorpel zu bilden, (ii) eine integrative Phasengrenzgewebe mit dem darunterliegenden Knochengewebe zu bilden, welches aus osteogenen OA Zellen hergestellt wurde, (iii) die Reparatur von OA-induzierten Defekten in artikulären Gelenken von Schafen zu fördern. NC und AC (artikuläre Chondrozyten, Kontrolle) vom gleichen Spender (OA/gesund) werden IL1b und/oder TNFa unter geläufigen statischen oder zyklischen kompressiven Deformationen (Bioreaktor) ausgesetzt. So wird untersucht, wie NC auf Faktoren, die typischerweise mit OA Erkrankung assoziiert sind, reagieren. Ausserdem werden die Chondrozyten mit inflammatorischen Monozyten oder OA-Synoviozyten in Transwells co-kultiviert, um zu untersuchen, wie von den inflammatorischen Zellen sekretierte Faktoren die chondrogene Differenzierungsfähigkeit der NC und AC beeinflussen. Des Weiteren werden NC vom Schaf (SNC) verwendet, um Knorpelgewebe herzustellen, welcher in OA-induzierte Defekte in den Kniegelenken des gleichen Tieres implantiert wird. Hierdurch soll ermittelt werden, ob autologe NC OA Defekte in artikulären Gelenken wirkungsvoll reparieren können. Die Ergebnisse dieses Projektes werden prä-klinischen Daten für die potentielle Nutzung von NC als alternative Zellquelle bei der Reparatur von OA Defekten liefern.

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Last update: 06.11.2013

Active participation

Number	Title	Start	Funding scheme

Background. Osteoarthritis (OA) is the most prevalent musculoskeletal disease in humans. It causes joint pain and loss of motility, which results in a reduction of the standard life for millions of people world-wide. The implantation of autologous articular chondrocytes (AC) is an established surgical approach for the treatment of traumatic but not yet osteoarthritic lesions. This cell-based therapy indeed results in an unpredictable outcome when applied for the treatment of patients with chronic cartilage defects, probably because of the poor quality of the AC isolated from their joints. Nasal chondrocytes (NC) would represent an attractive cell source for the repair of OA cartilage defects due to their procurement from a ‘‘healthy” heterotopic compartment. Additionally NC have been demonstrated to have a more reproducible capacity to generate functional cartilaginous tissue, independent of the donor age, and respond similarly to AC to mechanical forces typical of joint loading. This study generally addresses the suitability of NC for the repair of OA cartilage defects. Working hypothesis. The working hypothesis of the proposed research is that NC are compatible in an OA joint environment. This compatibility is here defined by the capacity of nasal chondrocytes to (i) form stable cartilaginous tissue when exposed to biochemical and biomechanical signals simulating an OA joint environment, (ii) form an interface tissue enabling integration to bone generated by OA osteogenic cells, (iii) promote the repair of OA-induced defects in articular joints of sheep.Specific aims. We will first investigate the cytokine release profile and cartilage forming capacity of human NC (HNC) exposed to inflammatory signals and mechanical loading or cocultured with inflammatory monocytes or OA synoviocytes (Aim 1). We will then determine whether tissue formed by HNC can integrate with bone that would be formed by OA osteoblasts ectopically in nude mice (Aim 2). The performances of HNC will be compared to those of human AC (HAC) derived from the same donors. Finally we will verify whether the implantation of autologous NC grafts in OA defects induced in the knees of sheep can restore the articular joints of the animals (Aim 3).Experimental design. NC and AC (as control) isolated from the same donors (OA or healthy) will be exposed to IL-1beta and/or TNFalpha under conventional static condition or in a bioreactor system applying cyclic compressive deformation in order to study their response to factors typical of OA joints. Additionally chondrocytes will be cocultured with inflammatory monocytes or OA synoviocytes in transwell to investigate how factors released by these inflammatory cells influence HNC and HAC chondrogenesis. HNC-generated cartilage grafts will also be combined with hydroxyapatite-based scaffold containing OA osteoblast and implanted subcutaneously in nude mice to study the capacity of HNC to form a stable cartilage and to integrate with newly formed bone tissue. Furthermore, sheep NC (SNC) will be labelled with GFP and used to generate cartilaginous tissue that will be implanted into OA defects induced in the knees of sheep. This model will determine whether autologous NC can efficiently repair osteoarthritic joint defects. Expected value of the proposed project. The proposed research will acquire crucial information about the biology of nasal chondrocytes and their response to specific in vitro conditions mimicking the osteoarthritic joint environment. Moreover it will provide the necessary pre-clinical data for the potential use of NC as a cell source for the repair of OA cartilage lesions. We envision that at the end of the project a pilot clinical trial for the treatment of OA articular cartilage lesions with NC could be planned. In this regards, we will consider to implant engineered cartilaginous tissues based of autologous NC in combination with standard surgical intervention allowing to restore the etiology of the disease (e.g., joint kinematics and biomechanics).