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Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.

ABSTRACT: BACKGROUND:Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in the knee joint. METHODS:The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosaminoglycan (sGAG). The mono-iodoacetate (MIA)-induced preclinical model of OA has been used to demonstrate pain reduction and cartilage formation. In the clinical study, 60 OA patients were randomized to receive different doses of cells (25, 50, 75, or 150 million cells) or placebo. Stempeucel® was administered by intra-articular (IA) injection into the knee joint, followed by 2 ml hyaluronic acid (20 mg). Subjective evaluations-visual analog scale (VAS) for pain, intermittent and constant osteoarthritis pain (ICOAP), and Western Ontario and McMaster Universities Osteoarthritis (WOMAC-OA) index-were performed at baseline and at 1, 3, 6, and 12 months of follow-up. Magnetic resonance imaging of the knee was performed at baseline, and at 6 and 12 months follow-up for cartilage evaluation. RESULTS:Stempeucel® differentiated into the chondrogenic lineage in vitro with downregulation of Sox9 and upregulation of Col2A genes. Furthermore, Stempeucel® differentiated into chondrocytes and synthesized a significant amount of sGAG (30?±?1.8 ?g/?g GAG/DNA). In the preclinical model of OA, Stempeucel® reduced pain significantly and also repaired damaged articular cartilage in rats. In the clinical study, IA administration of Stempeucel® was safe, and a trend towards improvement was seen in the 25-million-cell dose group in all subjective parameters (VAS, ICOAP, andWOMAC-OA scores), although this was not statistically significant when compared to placebo. Adverse events were predominant in the higher dose groups (50, 75, and 150 million cells). Knee pain and swelling were the most common adverse events. The whole-organ magnetic resonance imaging score of the knee did not reveal any difference from baseline and the placebo group. CONCLUSION:Intra-articular administration of Stempeucel® is safe. A twenty-five-million-cell dose may be the most effective among the doses tested for pain reduction. Clinical studies with a larger patient population are required to demonstrate a robust therapeutic efficacy of Stempeucel® in OA. TRIAL REGISTRATION:Clinicaltrials.gov NCT01453738 . Registered 13 October 2011.

SUBMITTER: Gupta PK

PROVIDER: S-EPMC5168586 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.

Gupta Pawan Kumar PK Chullikana Anoop A Rengasamy Mathiyazhagan M Shetty Naresh N Pandey Vivek V Agarwal Vikas V Wagh Shrikant Yeshwant SY Vellotare Prasanth Kulapurathu PK Damodaran Devi D Viswanathan Pachaiyappan P Thej Charan C Balasubramanian Sudha S Majumdar Anish Sen AS

Arthritis research & therapy 20161220 1

<h4>Background</h4>Osteoarthritis (OA) is a common and debilitating chronic degenerative disease of the joints. Currently, cell-based therapy is being explored to address the repair of damaged articular cartilage in the knee joint.<h4>Methods</h4>The in vitro differentiation potential of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®) was determined by differentiating the cells toward the chondrogenic lineage and quantifying sulfated glycosam ...[more]

PMID: 27993154

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Project description:Osteoarthritis (OA) is the most common musculoskeletal disorder. Although joint replacement remains the standard of care for knee OA patients, knee joint distraction (KJD), which works by temporarily off-loading the joint for 6-8 weeks, is becoming a novel joint-sparing alternative for younger OA sufferers. The biological mechanisms behind KJD structural improvements remain poorly understood but likely involve joint-resident regenerative cells including multipotent stromal cells (MSCs). In this study, we hypothesized that KJD leads to beneficial cartilage-anabolic and anti-catabolic changes in joint-resident MSCs and investigated gene expression profiles of synovial fluid (SF) MSCs following KJD as compared with baseline. To obtain further insights into the effects of local biomechanics on MSCs present in late OA joints, SF MSC gene expression was studied in a separate OA arthroplasty cohort and compared with subchondral bone (SB) MSCs from medial (more loaded) and lateral (less loaded) femoral condyles from the same joints. In OA arthroplasty cohort (n = 12 patients), SF MSCs expressed lower levels of ossification- and hypotrophy-related genes [bone sialoprotein (IBSP), parathyroid hormone 1 receptor (PTH1R), and runt-related transcription factor 2 (RUNX2)] than did SB MSCs. Interestingly, SF MSCs expressed 5- to 50-fold higher levels of transcripts for classical extracellular matrix turnover molecules matrix metalloproteinase 1 (MMP1), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), and tissue inhibitor of metalloproteinase-3 (TIMP3), all (p < 0.05) potentially indicating greater cartilage remodeling ability of OA SF MSCs, compared with SB MSCs. In KJD cohort (n = 9 patients), joint off-loading resulted in sustained, significant increase in SF MSC colonies' sizes and densities and a notable transcript upregulation of key cartilage core protein aggrecan (ACAN) (weeks 3 and 6), as well as reduction in pro-inflammatory C-C motif chemokine ligand 2 (CCL2) expression (weeks 3 and 6). Additionally, early KJD changes (week 3) were marked by significant increases in MSC chondrogenic commitment markers gremlin 1 (GREM1) and growth differentiation factor 5 (GDF5). In combination, our results reveal distinct transcriptomes on joint-resident MSCs from different biomechanical environments and show that 6-week joint off-loading leads to transcriptional changes in SF MSCs that may be beneficial for cartilage regeneration. Biomechanical factors should be certainly considered in the development of novel MSC-based therapies for OA.

Project description:Purpose ?The aim of the study was to evaluate the clinical effects of HYADD® 4, an hydrogel based on a hyaluronic acid derivative, in patients with symptomatic knee osteoarthritis, on symptoms, and joint function. Methods ?This retrospective study of patients with Kellgren-Lawrence grade II to IV knee osteoarthritis (American College of Rheumatology criteria) enrolled patients who had received two infiltrations of HYADD® 4, (24 mg/3 mL) 1?week apart, and evaluated: pain at rest, pain with movement, change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score; change in nonsteroidal anti-inflammatory drugs (NSAIDs)/acetaminophen use; satisfaction with therapy; tolerability. Study duration was 6 months for all predefined endpoints, with a 6-month extension for pain symptoms only. Results ?After 6 months, all predefined endpoints were evaluable in 698 of 937 enrolled patients (74.5%). Mean WOMAC scores were reduced by 56.3% from baseline ( p ?<?0.05). NSAIDs/acetaminophen use ?2 times/week (48.8% of patients at baseline) was substantially reduced after 1?month and was 19.6% after 6 months. After 6 months, 85.6% of patients were satisfied about efficacy. There were no significant adverse effects. The effect on resting pain was rapid, strong, and lasting: reduction from baseline was 45.1% at 1?month ( p ?<?0.05), 56.8% at 6 months ( p ?<?0.05), and 53.6% at 12 months ( p ?<?0.05). Pain on moving was reduced by 47.4% after 6 months ( p ?<?0.05) and 46.0% after 12 months ( p ?<?0.05), results at 6 and 12 months were similar. Conclusion ?HYADD® 4 is a new-generation hyaluronic acid with distinctive viscoelastic and rheological properties. In patients with mild-to-severe knee OA (Kellgren-Lawrence grades II-IV), two consecutive infiltrations 1?week apart reduced WOMAC scores and NSAIDs/acetaminophen consumption for at least 6 months. In a subpopulation ( n ?=?106), efficacy on pain lasted approximately 12 months. Adverse events were reported in 11.2% of patients; the most frequent were arthralgias. No cases of allergic reactions or systemic effects were recorded. Level of Evidence ?Level IV, retrospective case series.

Project description:Objectives:The aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA). Methods:The expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo. Results:In total, 739 mRNAs, 1152 lncRNAs, and 42 circRNAs were found to be differentially expressed in OA cartilage tissue. Among these, we identified 18 overlapping DEGs and targets of DELs, and the top ten DELs were screened by expression profile analysis as candidate OA-related genes. WISP2, ATF3, and CHI3L1 were significantly increased in both normal versus OA tissues and normal versus interleukin (IL)-1?-induced OA-like cell models, while ADAM12, PRELP, and ASPN were shown to be significantly decreased. Among the identified DELs, we observed higher expression of ENST00000453554 and MSTRG.99593.3, and lower expression of MSTRG.44186.2 and NONHSAT186094.1 in normal versus OA cells and tissues. Conclusion:This study revealed expression patterns of coding and noncoding RNAs in OA cartilage, which added sets of genes and noncoding RNAs to the list of candidate diagnostic biomarkers and therapeutic agents for OA patients.Cite this article: H. Li, H. H. Yang, Z. G. Sun, H. B. Tang, J. K. Min. Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res 2019;8:288-301. DOI: 10.1302/2046-3758.86.BJR-2018-0297.R1.

Project description:ObjectivesThe aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA).MethodsThe expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo.ResultsIn total, 739 mRNAs, 1152 lncRNAs, and 42 circRNAs were found to be differentially expressed in OA cartilage tissue. Among these, we identified 18 overlapping DEGs and targets of DELs, and the top ten DELs were screened by expression profile analysis as candidate OA-related genes. WISP2, ATF3, and CHI3L1 were significantly increased in both normal versus OA tissues and normal versus interleukin (IL)-1β-induced OA-like cell models, while ADAM12, PRELP, and ASPN were shown to be significantly decreased. Among the identified DELs, we observed higher expression of ENST00000453554 and MSTRG.99593.3, and lower expression of MSTRG.44186.2 and NONHSAT186094.1 in normal versus OA cells and tissues.ConclusionThis study revealed expression patterns of coding and noncoding RNAs in OA cartilage, which added sets of genes and noncoding RNAs to the list of candidate diagnostic biomarkers and therapeutic agents for OA patients.Cite this article: H. Li, H. H. Yang, Z. G. Sun, H. B. Tang, J. K. Min. Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res 2019;8:290-303. DOI: 10.1302/2046-3758.87.BJR-2018-0297.R1.

Project description:Anterior cruciate ligament (ACL) injury predisposes individuals to early-onset knee joint osteoarthritis (OA). Abnormal joint loading is apparent after ACL injury and reconstruction. The relationship between altered joint biomechanics and the development of knee OA is unknown.Altered knee joint kinetics and medial compartment contact forces initially after injury and reconstruction are associated with radiographic knee OA 5 years after reconstruction.Case-control study; Level of evidence, 3.Individuals with acute, unilateral ACL injury completed gait analysis before (baseline) and after (posttraining) preoperative rehabilitation and at 6 months, 1 year, and 2 years after reconstruction. Surface electromyographic and knee biomechanical data served as inputs to an electromyographically driven musculoskeletal model to estimate knee joint contact forces. Patients completed radiographic testing 5 years after reconstruction. Differences in knee joint kinetics and contact forces were compared between patients with and those without radiographic knee OA.Patients with OA walked with greater frontal plane interlimb differences than those without OA (nonOA) at baseline (peak knee adduction moment difference: 0.00 ± 0.08 N·m/kg·m [nonOA] vs -0.15 ± 0.09 N·m/kg·m [OA], P = .014; peak knee adduction moment impulse difference: -0.001 ± 0.032 N·m·s/kg·m [nonOA] vs -0.048 ± 0.031 N·m·s/kg·m [OA], P = .042). The involved limb knee adduction moment impulse of the group with osteoarthritis was also lower than that of the group without osteoarthritis at baseline (0.087 ± 0.023 N·m·s/kg·m [nonOA] vs 0.049 ± 0.018 N·m·s/kg·m [OA], P = .023). Significant group differences were absent at posttraining but reemerged 6 months after reconstruction (peak knee adduction moment difference: 0.02 ± 0.04 N·m/kg·m [nonOA] vs -0.06 ± 0.11 N·m/kg·m [OA], P = .043). In addition, the OA group walked with lower peak medial compartment contact forces of the involved limb than did the group without OA at 6 months (2.89 ± 0.52 body weight [nonOA] vs 2.10 ± 0.69 body weight [OA], P = .036).Patients who had radiographic knee OA 5 years after ACL reconstruction walked with lower knee adduction moments and medial compartment joint contact forces than did those patients without OA early after injury and reconstruction.

Dataset Information

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.

Publications

Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint.

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