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Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo.

ABSTRACT: Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characterize the temporal ECM remodeling of human knee OA articular cartilage in response to sprifermin treatment. Articular cartilage explants from patients with knee OA (npatients?=?14) were cultured for 70 days, with permanent exposure to sprifermin (900, 450, 225?ng/mL), FGF18 (450?ng/mL), insulin-like growth factor-1 (100?ng/mL, positive control) or vehicle (nreplicates/treatment/patient?=?2). Metabolic activity (AlamarBlue) and biomarkers of type IIB collagen (PIIBNP) formation (Pro-C2 enzyme-linked immunosorbent assay [ELISA]) and aggrecanase-mediated aggrecan neo-epitope NITEGE (AGNx1 ELISA) were quantified once a week. At end of culture (day 70), gene expression (quantitative reverse transcription polymerase chain reaction) and proteoglycan content (Safranin O/Fast green staining) were quantified. The cartilage had continuously increased metabolic activity, when treated with sprifermin/FGF18 compared to vehicle. During days 7-28 PIIBNP was decreased and NITEGE was increased, and during days 35-70 PIIBNP was increased. At end of culture, the cartilage had sustained proteoglycan content and relative expression of ACAN?

SUBMITTER: Reker D

PROVIDER: S-EPMC7138815 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo.

Reker D D Siebuhr A S AS Thudium C S CS Gantzel T T Ladel C C Michaelis M M Aspberg A A Berchtold M W MW Karsdal M A MA Gigout A A Bay-Jensen A C AC

Scientific reports 20200407 1

Sprifermin, recombinant human fibroblast growth factor 18 (rhFGF18), induces cartilage regeneration in knees of patients with osteoarthritis (OA). We hypothesized that a temporal multiphasic process of extracellular matrix (ECM) degradation and formation underlie this effect. We aimed to characterize the temporal ECM remodeling of human knee OA articular cartilage in response to sprifermin treatment. Articular cartilage explants from patients with knee OA (n<sub>patients</sub> = 14) were culture ...[more]

PMID: 32265494

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Project description:BackgroundSprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential disease-modifying osteoarthritis drug (DMOAD). In vitro studies have shown that cartilage regenerative properties of sprifermin involve chondrocyte proliferation and extracellular matrix (ECM) production. To gain further insight into the process of sprifermin in the cartilage tissue, this study aimed at investigating the ECM turnover of articular cartilage explants in a longitudinal manner.MethodsBovine full-depth articular cartilage explants were stimulated with sprifermin or placebo at weekly intervals, similar to the dosing regimen used in clinical trials. Pre-culturing with oncostatin M and tumour necrosis factor-α, was also used to induce an inflammatory state before treatment. Metabolic activity was measured using AlamarBlue, and chondrocyte proliferation was visualized by immuno-histochemical detection of proliferating cell nuclear antigen. ECM turnover was quantified by biomarker ELISAs; ProC2 reflecting type II collagen formation, CS846 reflecting aggrecan formation, active MMP9, C2M and AGNx2 reflecting matrix metalloproteinase activity, and AGNx1 reflecting aggrecanase activity.ResultsSprifermin was able to reach the chondrocytes through the extracellular matrix, as it increased cell proliferation and metabolic activity of explants. ProC2 and CS846 was dose-dependently increased (P < 0.05) by sprifermin compared to placebo, while C2M and AGNx2 were unaffected, active MMP9 was slightly decreased, and AGNx1 was slightly increased. Over the course of treatment, the temporal order of ECM turnover responses was AGNx1, then ProC2, followed by CS846 and MMP9. Pro-inflammatory activation of the explants diminished the ECM turnover responses otherwise observed under non-inflammatory conditions.ConclusionsThe data suggest that sprifermin has chondrogenic effects on articular cartilage ex vivo, exerted through a sequential process of ECM turnover; aggrecan degradation seems to occur first, while type II collagen and aggrecan production increased at a later time point. In addition, it was observed that these chondrogenic effects are dependent on the inflammatory status of the cartilage prior to treatment.

Project description:AimsTo investigate the impact of subchondral bone cysts (SBCs) in stress-induced osseous and articular variations in cystic and non-cystic knee models using finite element analysis.Materials and methods3D knee joint models were reconstructed from computed tomography (CT) and magnetic resonance imaging (MRI). Duplicate 3D models were also created with a 3D sphere mimicking SBCs in medial tibia. Models were divided into three groups. In group A, a non-cystic knee model was used, whereas in groups B and C, SBCs of 4 and 12 mm size were simulated, respectively. Cyst groups were further divided into three sub-groups. Each of sub-group 1 was composed of a solitary SBC in the anterior half of tibia adjacent to joint line. In sub-group 2, a solitary cyst was modeled at a lower-joint location, and in sub-group 3, two SBCs were used. All models were vertically loaded with weights representing double- and single-leg stances.ResultsDuring single-leg stance, increase in subchondral bone stress in sub-groups B-1 and B-3 were significant (p = 0.044, p = 0.026). However, in sub-group B-2, a slight increase was observed than non-cystic knee model (9.93 ± 1.94 vs. 9.35 ± 1.85; p = 0.254). All the sub-groups in group C showed significantly increased articular stress (p < 0.001). Conversely, a prominent increase in peri-cystic cancellous bone stress was produced by SBCs in groups B and C (p < 0.001). Mean cartilage shear stress in sub-groups B-1 and B-2 (0.66 ± 0.56, 0.58 ± 0.54) was non-significant (p = 0.374, p = 0.590) as compared to non-cystic model (0.47 ± 0.67). But paired cysts of the same size (B-3) produced a mean stress of 0.98 ± 0.49 in affected cartilage (p = 0.011). Models containing 12 mm SBCs experienced a significant increase in cartilage stress (p = 0.001, p = 0.006, p < 0.001) in sub-groups C-1, C-2, and C-3 (1.25 ± 0.69, 1.01 ± 0.54, and 1.26 ± 0.59), respectively.ConclusionThe presence of large-sized SBCs produced an increased focal stress effect in articular cartilage. Multiple cysts further deteriorate the condition by increased osseous stress effect and high tendency of peripheral cyst expansion in simulated cystic knee models than non-cystic knee models.

Project description:ImportanceSprifermin is under investigation as a disease-modifying osteoarthritis drug.ObjectiveTo evaluate the effects of sprifermin on changes in total femorotibial joint cartilage thickness in the more symptomatic knee of patients with osteoarthritis.Design, setting, and participantsFORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) was a 5-year, dose-finding, multicenter randomized clinical trial conducted at 10 sites. Eligible participants were aged 40 to 85 years with symptomatic, radiographic knee osteoarthritis and Kellgren-Lawrence grade 2 or 3. Enrollment began in July 2013 and ended in May 2014; the last participant visit occurred on May 8, 2017. The primary outcome at 2 years and a follow-up analysis at 3 years are reported.InterventionsParticipants were randomized to 1 of 5 groups: intra-articular injections of 100 μg of sprifermin administered every 6 months (n = 110) or every 12 months (n = 110), 30 μg of sprifermin every 6 months (n = 111) or every 12 months (n = 110), or placebo every 6 months (n = 108). Each treatment consisted of weekly injections over 3 weeks.Main outcomes and measuresThe primary end point was change in total femorotibial joint cartilage thickness measured by quantitative magnetic resonance imaging at 2 years. The secondary end points (of 15 total) included 2-year change from baseline in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. The minimal clinically important difference (MCID) is unknown for the primary outcome; for total WOMAC score in patients with hip and knee osteoarthritis, the absolute MCID is 7 U (95% CI, 4 to 10 U) and the percentage MCID is 14% (95% CI, 9% to 18%).ResultsAmong 549 participants (median age, 65.0 years; 379 female [69.0%]), 474 (86.3%) completed 2-year follow-up. Compared with placebo, the changes from baseline to 2 years in total femorotibial joint cartilage thickness were 0.05 mm (95% CI, 0.03 to 0.07 mm) for 100 μg of sprifermin administered every 6 months; 0.04 mm (95% CI, 0.02 to 0.06 mm) for 100 μg of sprifermin every 12 months; 0.02 mm (95% CI, -0.01 to 0.04 mm) for 30 μg of sprifermin every 6 months; and 0.01 mm (95% CI, -0.01 to 0.03 mm) for 30 μg of sprifermin every 12 months. Compared with placebo, there were no statistically significant differences in mean absolute change from baseline in total WOMAC scores for 100 μg of sprifermin administered every 6 months or every 12 months, or for 30 μg of sprifermin every 6 months or every 12 months. The most frequently reported treatment-emergent adverse event was arthralgia (placebo: n = 46 [43.0%]; 100 μg of sprifermin administered every 6 months: n = 45 [41.3%]; 100 μg of sprifermin every 12 months: n = 50 [45.0%]; 30 μg of sprifermin every 6 months: n = 40 [36.0%]; and 30 μg of sprifermin every 12 months: n = 48 [44.0%]).Conclusions and relevanceAmong participants with symptomatic radiographic knee osteoarthritis, the intra-articular administration of 100 μg of sprifermin every 6 or 12 months vs placebo resulted in an improvement in total femorotibial joint cartilage thickness after 2 years that was statistically significant, but of uncertain clinical importance; there was no significant difference for 30 μg of sprifermin every 6 or 12 months vs placebo. Durability of response also was uncertain.Trial registrationClinicalTrials.gov Identifier: NCT01919164.

Dataset Information

Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo.

Publications

Sprifermin (rhFGF18) versus vehicle induces a biphasic process of extracellular matrix remodeling in human knee OA articular cartilage ex vivo.

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