title: Activin A/BMP2 chimera AB235 drives efficient redifferentiation of long term cultured autologous chondrocytes.
abstract: Autologous chondrocyte implantation (ACI) depends on the quality and quantity of implanted cells and is hindered by the fact that chondrocytes cultured for long periods of time undergo dedifferentiation. Here we have developed a reproducible and efficient chondrogenic protocol to redifferentiate chondrocytes isolated from osteoarthritis (OA) patients. We used morphological, histological and immunological analysis together with a RT-PCR detection of collagen I and collagen II gene expression to show that chondrocytes isolated from articular cartilage biopsies of patients and subjected to long-term culture undergo dedifferentiation and that these cells can be redifferentiated following treatment with the chimeric Activin A/BMP2 ligand AB235. Examination of AB235-treated cell pellets in both in vitro and in vivo experiments revealed that redifferentiated chondrocytes synthesized a cartilage-specific extracellular matrix (ECM), primarily consisting of vertically-orientated collagen fibres and cartilage-specific proteoglycans. AB235-treated cell pellets also integrated into the surrounding subcutaneous tissue following transplantation in mice as demonstrated by their dramatic increase in size while non-treated control pellets disintegrated upon transplantation. Thus, our findings describe an effective protocol for the promotion of redifferentiation of autologous chondrocytes obtained from OA patients and the formation of a cartilage-like ECM that can integrate into the surrounding tissue in vivo.
authors.affiliation: Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain.|Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18012, Spain.|Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada-Univesity of Granada, Granada, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Jiménez
authors.affiliation: Department of Health Sciences, University of Jaén, Jaén E-23071, Spain.
authors.forename: E
authors.initials: E
authors.lastname: López-Ruiz
authors.affiliation: Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla CA 92037, California, USA.
authors.forename: W
authors.initials: W
authors.lastname: Kwiatkowski
authors.affiliation: Department of Orthopedic Surgery and Traumatology, Virgen de la Victoria University Hospital, Málaga, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Montañez
authors.affiliation: Department of Histology, Faculty of Medicine, University of Granada, E-18071 Granada, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Arrebola
authors.affiliation: Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain.|Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18012, Spain.|Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada-Univesity of Granada, Granada, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Carrillo
authors.affiliation: Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla CA 92037, California, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Gray
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla CA 92037, California, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Izpisua Belmonte
authors.affiliation: Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla CA 92037, California, USA.|Qualcomm Institute, Univ. California, San Diego, La Jolla, CA 92037, USA.
authors.forename: S
authors.initials: S
authors.lastname: Choe
authors.affiliation: Department of Health Sciences, University of Jaén, Jaén E-23071, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Perán
authors.affiliation: Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada E-18100, Spain.|Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada E-18012, Spain.|Biosanitary Institute of Granada (ibs.GRANADA), University Hospitals of Granada-Univesity of Granada, Granada, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Marchal
mesh_terms: D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000473:pathology* / Q000637:transplantation; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D010003:Osteoarthritis / Q000473:pathology / Q000628:therapy; D011509:Proteoglycans / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014182:Transplantation, Autologous; D014183:Transplantation, Heterologous
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D008024:Ligands; D011509:Proteoglycans; C422405:activin A; D028341:Activins; D003094:Collagen