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Table 1 Therapeutic strategies to augment cell-based cartilage repair

From: Major biological obstacles for persistent cell-based regeneration of articular cartilage

Impairment Pathomechanism Therapeutic strategy References
Differentiation insufficiencies Un- or dedifferentiated cells Timed growth factor release systems/gene delivery  
      TGF-β superfamily members [76,85,88,134]
      FGFs [131]
      SOX/Smads [119-121,124-126]
   Cell selection  
      Growth factor selection [52-54,64]
      Immunophenotype selection [41,46]
  Hypertrophic differentiation Inhibition of hypertrophy  
      BMP inhibitors: noggin, chordin, siRNAs [89,90,160]
      PTHrP/IHH [81,91-95]
      Wnt5a [29,103,163]
      No dexamethasone [75]
  Osteogenesis Inhibition of osteogenesis  
      BMP inhibitors (noggin, chordin), siRNAs [89,90,160]
      Establishment of a barrier/tidemark to bone [49,198]
  Senescence Senescence protection  
     Age    Low oxygen tension [107,110]
     Telomere erosion    Use of telomerized cells [117]
     Oxidative damage    Anti-oxidative selenoproteins, superoxide dismutase [115,117,118,151,187]
     Chemical stress    Anti-inflammatory agents (IL-1Ra, sIL-1R, sTNFR) [132,185-188,190,191,193-195]
     Mechanical stress    Mechanoprotection [157,168,169]
Cell loss Inefficient cell delivery Guided, homogeneous cell delivery [2,48]
  Apoptosis (NO induced, stress) Anti-apoptotic measures  
      Bcl-2, Bcl-XL, anti-FasL [151,161,162,164]
      Anti-inflammatory agents (see also above) [132,185-188,190,191,193-195]
      Anti-oxidative agents [115,117,118,151,187]
  Necrosis Necrosis  
     Age    Surgical protection (no needle stitches, no unnecessary harm to cartilage lesion borders) [2,48]
     Mechanical stress    Mechanoprotection [2,48;168,169]
     Chemical stress    Anti-inflammatory agents [132,185-188,190,191,193-195]
     Oxidative stress    Anti-oxidative agents [115,117,118,151,187]
Matrix degradation Matrix degradation Delivery of matrix components [197]
  Inflammation Anti-inflammatory agents (IL-1Ra, sIL-1R, ICE inhibitor, sTNFR, anti-TNF-antibodies, TACE inhibitor, TIMP-1, -2, MMP inhibitors, IL-4, -10, -11, -13, GFAT) [132,185-188,190,191,193-195]
  Mechanical stress (shear stresses, compressive forces) Mechanoprotection  
      No trauma [2,48;168,169]
      Avoidance of non-physiological loads [1,2,8,9,12,20]
      Establishment of correct knee axis and stability [1,2,8,9,12,20]
      Antioxidants [115,117,118,151,187]
Integration Cartilage to cartilage Cartilage matrix crosslinks [20,49,200-202]
  Cartilage to bone Tidemark formation [49,198]
   Stimulation of cell migration [27,29,66]
      Chondroblasts above tidemark  
      Osteoblasts below tidemark  
  1. BMP, bone morphogenetic protein; FasL, Fas-Ligand; FGF, fibroblast growth factor; GFAT, fructose-6-phosphatase amido transferase; ICE, IL-1 converting enzyme; IHH, indian hedgehog; IL, interleukin; IL-1Ra, IL-1 receptor antagonist; MMP, matrix metalloproteinase; NO, nitric oxide; PTHrP, parathyroid hormone related peptide; sIL-1R, soluble IL-1 receptor; siRNA, small interfering RNA; SOX, SRY (sex determining region Y)-box; sTNFR, soluble TNF receptor; TACE, TNF-alpha converting enzyme; TGF, transforming growth factor; TIMP, tissue inhibitor of matrix metalloproteinases; TNF, tumor necrosis factor.