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

Steinert, Andre F; Ghivizzani, Steven C; Rethwilm, Axel; Tuan, Rocky S; Evans, Christopher H; Nöth, Ulrich

doi:10.1186/ar2195

Arthritis Research & Therapy

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

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.

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ISSN: 1478-6362

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