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Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model
Sonia A Garcia1, Kimberly Wilson1, Ningfeng Tang1
1Department of Orthopaedics, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Abstract:
The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.
Insights
Palovarotene, a retinoic acid nuclear receptor gamma agonist, effectively inhibited pre-existing osteochondroma growth in mice. This drug’s action involves the Stat3 pathway, offering a new therapeutic strategy for osteochondromas.
Area of Science:
- Pharmacology
- Oncology
- Genetics
Background:
- Osteochondromas are benign bone tumors often presenting after initial formation.
- Preclinical research typically focuses on drug effects during tumor initiation, not on established tumors.
- Investigating treatments for pre-existing osteochondromas is crucial as patients seek clinical intervention for existing masses.
Purpose of the Study:
- To evaluate the efficacy of palovarotene, a retinoic acid nuclear receptor gamma (RARγ) agonist, against pre-existing osteochondromas.
- To explore the underlying molecular pathways, specifically the role of Stat3, in palovarotene's anti-tumor effects.
- To assess both systemic and local nanoparticle-based delivery methods for palovarotene.
Main Methods:
- Utilized a mouse model of multiple osteochondromas to test palovarotene's action on established tumors.
- Administered palovarotene systemically at escalating doses and via local nanoparticle (NP) delivery.
- Conducted transcriptome analysis on chondrocytes, reporter assays, immunoblotting, and immunohistochemistry to investigate pathway activation.
Main Results:
- Systemic palovarotene administration at doses up to 4.0 mg/kg fully inhibited osteochondroma growth, maintaining tumor size.
- Nanoparticle-based local delivery of the RARγ agonist also significantly inhibited early-stage osteochondroma growth.
- Transcriptome analysis indicated activation of the osteoarthritis pathway and Stat3 signaling by palovarotene, with Stat3 activation confirmed experimentally.
Conclusions:
- Palovarotene demonstrates significant efficacy in inhibiting the growth of pre-existing osteochondromas.
- The Stat3 signaling pathway is implicated in the anti-tumor mechanisms of palovarotene against osteochondromas.
- Both systemic and local NP delivery of palovarotene show therapeutic potential for managing osteochondroma progression.
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