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To investigate the effects of a Mediterranean type diet on patients with osteoarthritis (OA). Ninety-nine volunteers with OA (aged 31 - 90 years) completed the study (83% female). Southeast of England, UK. Participants were randomly allocated to the dietary intervention (DIET, n = 50) or control (CON, n = 49). The DIET group were asked to follow a Mediterranean type diet for 16 weeks whereas the CON group were asked to follow their normal diet. All participants completed an Arthritis Impact Measurement Scale (AIMS2) pre-, mid- and post- study period. A subset of participants attended a clinic at the start and end of the study for assessment of joint range of motion, ROM (DIET = 33, CON = 28), and to provide blood samples (DIET = 29, CON = 25) for biomarker analysis (including serum cartilage oligomeric matrix protein (sCOMP) (a marker of cartilage degradation) and a panel of other relevant biomarkers including pro- and anti-inflammatory cytokines). There were no differences between groups in the response of any AIMS2 components and most biomarkers (p > 0.05), except the pro-inflammatory cytokine IL-1α, which decreased in the DIET group (~47%, p = 0.010). sCOMP decreased in the DIET group by 1 U/L (~8%, p = 0.014). There was a significant improvement in knee flexion and hip rotation ROM in the DIET group (p < 0.05). The average reduction in sCOMP in the DIET group (1 U/L) represents a meaningful change, but the longer term effects require further study.

This phase I clinical trial evaluated the safety and clinical efficacy of adipose‐derived stromal cells (ASCs) in osteoarthritis. Eighteen patients with severe knee osteoarthritis were treated with a single intra‐articular injection of autologous ASCs at low (2 × 106 cells), medium (10 × 106), or high (50 × 106) doses (n = 6 each). After 6 months, no serious adverse events were reported, and patients treated with low‐dose ASCs significantly improved in pain and function. Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose‐escalation protocol of intra‐articular injected adipose‐derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra‐articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 106 cells), medium dose (10 × 106), and high dose (50 × 106). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow‐up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low‐dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra‐articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo‐controlled double‐blind phase IIb study is being initiated to assess clinical and structural efficacy. Significance Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose‐derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long‐term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.

Key Points Osteoarthritis (OA) is a whole-joint disease in which all of the components of the joint are affected The articular cartilage, subchondral bone, and calcified cartilage form an osteochondral biocomposite that is uniquely adapted to transferring loads during weight bearing and joint motion Marked alterations in the composition, functional properties, and structure of the osteochondral tissues occur during the evolution of OA Alteration in the composition or structure of any of the individual components of the osteochondral unit can initiate OA pathology in the joint The differential capacity of bone and cartilage to adapt to the effects of local mechanical and environmental influences has an important role in the development of OA Crosstalk between chondrocytes and bone cells contributes to OA pathogenesis To develop rational therapies for OA, it is essential to have diagnostic tools to define the state of the components of the osteochondral unit In this Review, the authors summarize the changes that occur in the biocomposite formed by articular cartilage and bone during the evolution of osteoarthritis (OA). They also discuss how an improved understanding of these changes could be exploited to develop new therapies for patients with OA. In diarthrodial joints, the articular cartilage, calcified cartilage, and subchondral cortical and trabecular bone form a biocomposite — referred to as the osteochondral unit — that is uniquely adapted to the transfer of load. During the evolution of the osteoarthritic process the compositions, functional properties, and structures of these tissues undergo marked alterations. Although pathological processes might selectively target a single joint tissue, ultimately all of the components of the osteochondral unit will be affected because of their intimate association, and thus the biological and physical crosstalk among them is of great importance. The development of targeted therapies against the osteoarthritic processes in cartilage or bone will, therefore, require an understanding of the state of these joint tissues at the time of the intervention. Importantly, these interventions will not be successful unless they are applied at the early stages of disease before considerable structural and functional alterations occur in the osteochondral unit. This Review describes the changes that occur in bone and cartilage during the osteoarthritic process, and highlights strategies for how this knowledge could be applied to develop new therapeutic interventions for osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative joint disease and a major health problem in the elderly population. No disease-modifying osteoarthritis drug (DMOAD) has been made available for clinical use. Here we present a disease-modifying strategy for OA, focusing on messenger RNA (mRNA) delivery of a therapeutic transcription factor using polyethylene glycol (PEG)-polyamino acid block copolymer-based polyplex nanomicelles. When polyplex nanomicelles carrying the cartilage-anabolic, runt-related transcription factor (RUNX) 1 mRNA were injected into mouse OA knee joints, OA progression was significantly suppressed compared with the non-treatment control. Expressions of cartilage-anabolic markers and proliferation were augmented in articular chondrocytes of the RUNX1 -injected knees. Thus, this study provides a proof of concept of the treatment of degenerative diseases such as OA by the in situ mRNA delivery of therapeutic transcription factors; the presented approach will directly connect basic findings on disease-protective or tissue-regenerating factors to disease treatment.

Background Extracts of chicory root have anti-inflammatory properties in vitro and in animal models of arthritis. The primary objective of this investigator-initiated, Phase 1, placebo-controlled, double blind, dose-escalating trial was to determine the safety and tolerability of a proprietary bioactive extract of chicory root in patients with osteoarthritis (OA). Secondary objectives were to assess effects on the signs and symptoms of this disorder. Methods Individuals greater than 50 years of age with OA of the hip or knee were eligible for trial entry. A total of 40 patients were enrolled in 3 cohorts and were treated with escalating chicory doses of 600 mg/day, 1200 mg/day and 1800 mg/day for 1 month. The ratio of active treatment to placebo was 5:3 in cohorts 1 and 2 (8 patients) each and 16:8 in cohort 3 (24 patients). Safety evaluations included measurement of vital signs and routine lab tests at baseline and the end of the treatment period. Efficacy evaluations at baseline and final visits included self-assessment questionnaires and measurement of the 25-foot walking time. Results In the highest dose cohort, 18 patients who completed treatment per protocol were analyzed for efficacy. In this group, 13 patients showed at least 20% improvement in the defined response domains of pain, stiffness and global assessment: 9 of 10 (90%) patients randomized to active treatment with chicory and 4 of 8 (50%) patients randomized to placebo (P = 0.06). In general, the treatment was well-tolerated. Only one patient who was treated with the highest dose of chicory had to discontinue treatment due to an adverse event. Conclusions The results of this pilot study suggest that a proprietary bioactive extract of chicory root has a potential role in the management of OA and merits further investigation. Clinicaltrials.gov identifier: NCT 01010919.

Background Mesenchymal stromal cells are a promising option to treat knee osteoarthritis. Their safety and usefulness must be confirmed and the optimal dose established. We tested increasing doses of bone marrow mesenchymal stromal cells (BM-MSCs) in combination with hyaluronic acid in a randomized clinical trial. Materials A phase I/II multicenter randomized clinical trial with active control was conducted. Thirty patients diagnosed with knee OA were randomly assigned to intraarticularly administered hyaluronic acid alone (control), or together with 10 × 10 6 or 100 × 10 6 cultured autologous BM-MSCs, and followed up for 12 months. Pain and function were assessed using VAS and WOMAC and by measuring the knee motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage. Results No adverse effects were reported after BM-MSC administration or during follow-up. BM-MSC-administered patients improved according to VAS during all follow-up evaluations and median value (IQR) for control, low-dose and high-dose groups change from 5 (3, 7), 7 (5, 8) and 6 (4, 8) to 4 (3, 5), 2 (1, 3) and 2 (0,4) respectively at 12 months (low-dose vs control group p = 0.005 and high-dose vs control group p < 0.009). BM-MSC-administered patients were also superior according to WOMAC, although improvement in control and low-dose patients could not be significantly sustained beyond 6 months. On the other hand, the BM-MSC high-dose group exhibited an improvement of 16.5 (12, 19) points at 12 months (p < 0.01). Consistent with WOMAC and VAS values, motion ranges remained unaltered in the control group but improved at 12 months with BM-MSCs. X-ray revealed a reduction of the knee joint space width in the control group that was not seen in BM-MSCs high-dose group. MRI (WORMS protocol) showed that joint damage decreased only in the BM-MSC high-dose group, albeit slightly. Conclusions The single intraarticular injection of in vitro expanded autologous BM-MSCs together with HA is a safe and feasible procedure that results in a clinical and functional improvement of knee OA, especially when 100 × 10 6 cells are administered. These results pave the way for a future phase III clinical trial. Clinical Trials.gov identifier NCT02123368. Nº EudraCT: 2009-017624-72

ObjectivesIn the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location.MethodsPatients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects.ResultsThinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects.ConclusionsSprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results.Trial registration number NCT01919164.

Background Human bone marrow is a source of mesenchymal stem cells (MSCs), other progenitor cells, and factors with anti-inflammatory and regenerative capacity. Though the fraction of MSCs out of the nucleated cells is very small, bone marrow aspirate (BMA) for osteoarthritis (OA) has noteworthy effects. BMA is usually collected from the posterior or anterior iliac crest, and rarely from the proximal tibia. We investigated the clinically beneficial concentration of ex vivo MSCs, derived from BM harvested from the posterior iliac crest and proximal tibia by Marrow Cellution™ Aspiration System, and their phenotypic differences, in comparison to autologous Platelet-Rich Plasma (PRP) treatment prepared with a manual, closed system. Methods A single-center, parallel, randomized controlled study was designed to investigate the efficacy of BMA from the posterior iliac crest compared to BMA from the proximal tibia, against a control group treated with PRP, in knee OA. Thirty patients with knee OA grade I-IV, according to Kellgren-Lawrence (KL), were distributed into each group. Visual Analog Scale (VAS) and Western Ontario & McMaster Universities Arthritis Index (WOMAC) score were used for clinical outcome evaluation. Results Data from an intermediate analysis of 6-months follow-up, involving 15 patients in each arm, showed that the posterior iliac crest was significantly more densely populated with mononuclear cells, than the proximal tibia (p = 0.005). Flow cytometric analysis on ex vivo BMA showed a significantly greater number of MSCs in the BM-derived from the posterior iliac crest when compared with the proximal tibia (p < 0.001), together with a significantly higher number of platelets (PLTs) (p < 0.001). Surprisingly, despite these differences in cells number, the improvement in early pain and function scores, after each treatment, were statistically significant within each of the three arms. BM from the proximal tibia showed the highest ΔWOMAC, while BM from the posterior iliac crest showed the highest ΔVAS; however, these differences were not statistically significant across the three arms (p > 0.05). A better outcome, in terms of ΔVAS, was observed in patients classified as KL I-II, when treated with BMA from crest (p < 0.001) and PRP (p = 0.004). Moreover, the effect of BMA treatment on ΔVAS depends on MSCs % only in the Tibia Arm (r = -0.59, p = 0.021), where we also found a correlation between ΔWOMAC and monocytes (r = 0.75, p = 0.016). Conclusion The results indicate that the iliac crest yields a higher concentration of MSCs compared to the proximal tibia, however both BM, independently of the MSCs concentration, show a beneficial clinical outcome in the treatment of knee OA. Furthermore, BMA is not superior to PRP treatment.

This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis. Safety and efficacy of haMSCs were preclinically assessed and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 × 10 , 2 × 10 and 5 × 10 cells, respectively), provided three injections and followed up for 96 weeks. The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 × 10 haMSCs exhibited the highest improvement (ClinicalTrials.gov Identifier: NCT01809769).

To establish a histopathological scoring system for changes in subchondral bone in murine models of knee osteoarthritis (OA), three key parameters, subchondral bone plate (Subcho.BP) consisting of the combination of Subcho.BP.thickness (Subcho.BP.Th) and angiogenesis, bone volume (BV/TV) and osteophytes, were selected. The new grading system was tested in two mouse OA models, (1) senescence accelerated mouse (SAM)-prone 8 (SAMP8) as spontaneous OA model with SAM-resistant 1 (SAMR1) as control; (2) destabilization of the medial meniscus in C57BL/6 mice as surgical OA model. Results of the spontaneous OA model showed that Subcho.BP.Th was significantly wider, angiogenesis was greater, and BV/TV was higher in SAMP8 than SAMR1. Notably, subchondral bone score was dramatically higher in SAMP8 at 6 weeks than SAMR1, while OARSI cartilage scores became higher only at 14 weeks. In the surgical OA model, the results were similar to the spontaneous OA model, but osteophytes appeared earlier. There were strong correlations both in Subcho.BP.Th and BV/TV between this scoring system and µCT (r = 0.89, 0.84, respectively). Inter-rater reliabilities for each parameter using this system were more than 0.943. We conclude that this new histopathological scoring system is readily applicable for evaluating the early changes in aging and OA-affected murine subchondral bone.