Umbilical Cord-Derived Stem Cells for the Treatment of Knee Osteoarthritis: A Systematic Review.

Background: The use of mesenchymal stem cells (MSCs) for the treatment of knee osteoarthritis (OA) has gained recent interest in the orthopaedics community. Purpose: To review the literature to evaluate the efficacy of umbilical cord-derived MSCs in the treatment of OA of the knee joint. Study Design: Systematic review; Level of evidence, 4. Methods: We searched the PubMed, Cochrane Library, and Embase databases to identify studies with evidence levels from 1 to 4 that evaluated the clinical efficacy of human umbilical cord-derived MSC (hUC-MSC) injections for knee OA. The search phrase used was "umbilical cord knee osteoarthritis." In the studies reviewed, patients were assessed based on the macroscopic International Cartilage Regeneration & Joint Preservation Society (ICRS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain, and the subjective International Knee Documentation Committee (IKDC) score. Results: A total of 7 studies met inclusion criteria, including 385 patients undergoing injection of hUC-MSCs (mean age, 59.7 years). The mean follow-up was 23.4 months. Weighted averages of the WOMAC, macroscopic ICRS, subjective IKDC, and VAS scores all showed improvement from before to after treatment. No severe adverse reactions were recorded. Conclusion: Patients undergoing treatment of knee OA with hUC-MSCs might be expected to experience improvements in clinical outcomes. Additional high-quality randomized studies are needed to better determine the efficacy of hUC-MSC for the treatment of knee OA.

Third-Generation Autologous Chondrocyte Implantation (Cells Cultured Within Collagen Membrane) Is Superior to Microfracture for Focal Chondral Defects of the Knee Joint: Systematic Review and Meta-analysis.

PURPOSE: To systematically review randomized controlled trials to compare clinical outcomes of microfracture (MFx) versus third-generation autologous chondrocyte implantation (ACI) for the treatment of focal chondral defects (FCDs) of the knee joint. METHODS: A systematic review was performed by searching PubMed, Cochrane Library, and EMBASE to locate randomized controlled trials comparing minimum 2-year clinical outcomes of patients undergoing MFx versus third-generation ACI for FCDs of the knee joint. The search terms used were: "knee" AND "microfracture" AND "autologous chondrocyte" AND "randomized." Patients were evaluated based on treatment failure rates, magnetic resonance imaging, International Cartilage Repair Society scores, and patient-reported outcome scores (Lysholm, Tegner, Knee Injury and Osteoarthritis Outcome Score, modified Cincinnati Knee Rating System, 12-item Short Form Health Survey Physical and Mental, and the EuroQol 5 Dimensions Visual Analog Scale score). RESULTS: Six studies (5 Level I, 1 Level II) met inclusion criteria, including a total of 238 patients undergoing MFx and 274 undergoing ACI. Two studies had an overlapping cohort of patients and therefore the study with longer follow-up was used in all analyses. The average follow-up among patients ranged from 2.0 years to 6.0 years. Average lesion size ranged from 1.8 cm2 to 5.0 cm2. Treatment failure ranged from 0% to 1.8% in the ACI group and 2.5% to 8.3% in the MFx group. In 4 studies, ACI patients demonstrated significantly greater improvement in multiple Knee Injury and Osteoarthritis Outcome Score subscores compared with MFx. In 2 studies, patients who received ACI demonstrated significantly greater improvement in the Tegner score compared to MFx, and 1 study showed significantly greater improvement in the Lysholm and ICRS scores for ACI compared with MFx. CONCLUSIONS: At short-term follow-up, third-generation ACI demonstrates a lower failure rate and greater improvement in patient-reported outcomes compared with MFx for FCDs of the knee joint. LEVEL OF EVIDENCE: II, systematic review of Levels I-II studies.

Functional dissection of the cis-acting sequences of the Arabidopsis transposable element Tag1 reveals dissimilar subterminal sequence and minimal spacing requirements for transposition.

The Arabidopsis transposon Tag1 has an unusual subterminal structure containing four sets of dissimilar repeats: one set near the 5' end and three near the 3' end. To determine sequence requirements for efficient and regulated transposition, deletion derivatives of Tag1 were tested in Arabidopsis plants. These tests showed that a 98-bp 5' fragment containing the 22-bp inverted repeat and four copies of the AAACCX (X = C, A, G) 5' subterminal repeat is sufficient for transposition while a 52-bp 5' fragment containing only one copy of the subterminal repeat is not. At the 3' end, a 109-bp fragment containing four copies of the most 3' repeat TGACCC, but not a 55-bp fragment, which has no copies of the subterminal repeats, is sufficient for transposition. The 5' and 3' end fragments are not functionally interchangeable and require an internal spacer DNA of minimal length between 238 and 325 bp to be active. Elements with these minimal requirements show transposition rates and developmental control of excision that are comparable to the autonomous Tag1 element. Last, a DNA-binding activity that interacts with the 3' 109-bp fragment but not the 5' 98-bp fragment of Tag1 was found in nuclear extracts of Arabidopsis plants devoid of Tag1.

Temperature-sensitive mutations in the Saccharomyces cerevisiae MRT4, GRC5, SLA2 and THS1 genes result in defects in mRNA turnover.

In a screen for factors involved in mRNA turnover, four temperature-sensitive yeast strains (ts1189, ts942, ts817, and ts1100) exhibited defects in the decay of several mRNAs. Complementation of the growth and mRNA decay defects, and genetic experiments, revealed that ts1189 is mutated in the previously unknown MRT4 gene, ts942 is mutated in GRC5 (encoding the L9 ribosomal protein), ts817 contains a mutation in SLA2 (encoding a membrane protein), and ts1100 contains a mutation in THS1 (encoding the threonyl-tRNA synthetase). Three of the four mutants (mrt4, grc5, and sla2) were not defective in protein synthesis, suggesting that these strains contain mutations in factors that may play a specific role in mRNA decay. The mRNA stabilization observed in the ths1 strain, however, could be due to the significant drop in translation observed in this mutant at 37 degrees. While the three interesting mutants appear to encode novel mRNA decay factors, at least one could be linked to a previously characterized mRNA decay pathway. The growth and mRNA decay defects of ts942 (grc5) cells were suppressed by overexpression of the NMD3 gene, encoding a protein shown to participate in a two-hybrid interaction with the nonsense-mediated decay protein Upf1p.

Overexpression of truncated Nmd3p inhibits protein synthesis in yeast.

The yeast NMD3 gene was identified in a two-hybrid screen using the nonsense-mediated mRNA decay factor, Upf1p, as bait. NMD3 was shown to encode an essential, highly conserved protein that associated principally with free 60S ribosomal subunits. Overexpression of a truncated form of Nmd3p, lacking 100 C-terminal amino acids and most of its Upf1p-interacting domain, had dominant-negative effects on both cell growth and protein synthesis and promoted the formation of polyribosome half-mers. These effects were eliminated by truncation of an additional 100 amino acids from Nmd3p. Overexpression of the nmd3delta100 allele also led to increased synthesis and destabilization of some ribosomal protein mRNAs, and increased synthesis and altered processing of 35S pre-rRNA. Our data suggest that Nmd3p has a role in the formation, function, or maintenance of the 60S ribosomal subunit and may provide a link for Upf1p to 80S monosomes.