Dataset Information

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis.

ABSTRACT: Osteoarthritis (OA) affects nearly 10% of the population of the United States and other industrialized countries and, at present, short of surgical joint replacement, there is no therapy available that can reverse the progression of the disease. Adenosine, acting at its A2A receptor (A2AR), is a critical autocrine factor for maintenance of cartilage homeostasis and here we report that injection of liposomal suspensions of either adenosine or a selective A2AR agonist, CGS21680, significantly reduced OA cartilage damage in a murine model of obesity-induced OA. The same treatment also improved swelling and preserved cartilage in the affected knees in a rat model of established post-traumatic OA (PTOA). Differential expression analysis of mRNA from chondrocytes harvested from knees of rats with PTOA treated with liposomal A2AR agonist revealed downregulation of genes associated with matrix degradation and upregulation of genes associated with cell proliferation as compared to liposomes alone. Studies in vitro and in affected joints demonstrated that A2AR ligation increased the nuclear P-SMAD2/3/P-SMAD1/5/8 ratio, a change associated with repression of terminal chondrocyte differentiation. These results strongly suggest that targeting the A2AR is an effective approach to treat OA.

SUBMITTER: Corciulo C

PROVIDER: S-EPMC7418027 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis.

Corciulo Carmen C Castro Cristina M CM Coughlin Thomas T Jacob Samson S Li Zhu Z Fenyö David D Rifkin Daniel B DB Kennedy Oran D OD Cronstein Bruce Neil BN

Scientific reports 20200810 1

Osteoarthritis (OA) affects nearly 10% of the population of the United States and other industrialized countries and, at present, short of surgical joint replacement, there is no therapy available that can reverse the progression of the disease. Adenosine, acting at its A2A receptor (A2AR), is a critical autocrine factor for maintenance of cartilage homeostasis and here we report that injection of liposomal suspensions of either adenosine or a selective A2AR agonist, CGS21680, significantly redu ...[more]

PMID: 32778777

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Project description:ObjectiveTo determine whether an anabolic drug (sprifermin) is capable of reducing cartilage loss wherever it occurs in a given knee, using a subject-specific, location-independent analysis of cartilage change in patients with knee osteoarthritis (OA).MethodsStudy participants (n = 168; ages ≥40 years, 69% women) had symptomatic femorotibial OA not confined to the medial compartment. Sprifermin (10, 30, or 100 μg) or placebo was injected intraarticularly 3 times over 3 weeks, both after randomization (baseline) and 3 months later. Coronal magnetic resonance images were acquired at baseline and 3, 6, and 12 months after treatment. The femorotibial cartilage of each subject was segmented, and changes in cartilage thickness were computed across 16 subregions. Location-independent post hoc analysis was used to compute summary scores of negative and positive changes in the subregions, summarized as the total cartilage thinning sum score (ThCTnS) and the total cartilage thickening sum score (ThCTkS), capturing change in either direction in each knee. Ordered values of the magnitude of subject-specific subregional changes in thickness were determined. The ThCTnS and ThCTkS in each sprifermin dose group at 12 months of followup were compared with the values in the matched placebo groups, using the Wilcoxon-Mann-Whitney test.ResultsThe mean ± SD ThCTnS was -591 ± 617 μm (median -360 μm, Q1/Q3 = -820/-200 μm) in patients treated with 100 μg sprifermin (n = 57), and -921 ± 777 μm (median -745 μm, Q1/Q3 = -1,190/-380 μm) in patients given placebo (n = 18). The mean difference in the ThCTnS between the 100-μg sprifermin group and the placebo group was 331 μm (95% confidence interval [95% CI] 24, 685), a difference that was statistically significant (P = 0.03). The mean difference in the ThCTkS in the 100-μg sprifermin group compared with the placebo group was 237 μm (95% CI 34, 440), also a statistically significant difference (P = 0.028).ConclusionSprifermin not only increases cartilage thickness, but also reduces cartilage loss. Subject-specific, location-independent analysis of both cartilage thinning and thickening represents a sensitive and informative approach for studying the effects of disease-modifying OA drugs.

Dataset Information

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis.

Publications

Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis.

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