title: Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells.
abstract: Articular cartilage has a very limited intrinsic repair capacity leading to progressive joint damage. Therapies involving tissue engineering depend on chondrogenic differentiation of progenitor cells. This chondrogenic differentiation will have to survive in a diseased joint. We postulate that catabolic factors in this environment inhibit chondrogenesis of progenitor cells. We investigated the effect of a catabolic environment on chondrogenesis in pellet cultures of human mesenchymal stem cells (hMSCs). We exposed chondrogenically differentiated hMSC pellets, to interleukin (IL)-1α, tumor necrosis factor (TNF)-α or conditioned medium derived from osteoarthritic synovium (CM-OAS). IL-1α and TNF-α in CM-OAS were blocked with IL-1Ra or Enbrel, respectively. Chondrogenesis was determined by chondrogenic markers collagen type II, aggrecan, and the hypertrophy marker collagen type X on mRNA. Proteoglycan deposition was analyzed by safranin o staining on histology. IL-1α and TNF-α dose-dependently inhibited chondrogenesis when added at onset or during progression of differentiation, IL-1α being more potent than TNF-α. CM-OAS inhibited chondrogenesis on mRNA and protein level but varied in extent between patients. Inhibition of IL-1α partially overcame the inhibitory effect of the CM-OAS on chondrogenesis whereas the TNF-α contribution was negligible. We show that hMSC chondrogenesis is blocked by either IL-1α or TNF-α alone, but that there are additional factors present in CM-OAS that contribute to inhibition of chondrogenesis, demonstrating that catabolic factors present in OA joints inhibit chondrogenesis, thereby impairing successful tissue engineering.
authors.affiliation: Experimental Rheumatology and Advanced Therapeutics, St. Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
authors.forename: Genoveva T H
authors.initials: GT
authors.lastname: Heldens
authors.forename: Esmeralda N
authors.initials: EN
authors.lastname: Blaney Davidson
authors.forename: Elly L
authors.initials: EL
authors.lastname: Vitters
authors.forename: B Willem
authors.initials: BW
authors.lastname: Schreurs
authors.forename: Ester
authors.initials: E
authors.lastname: Piek
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Peter M
authors.initials: PM
authors.lastname: van der Kraan
mesh_terms: D000368:Aged; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D020219:Chondrogenesis / Q000187:drug effects*; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D005260:Female; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D055396:Bone Morphogenetic Protein 2; D017077:Culture Media, Conditioned; D053582:Interleukin-1alpha; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha