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Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice

Ruhang Tang, Natalia S. Harasymowicz, Chia-Lung Wu, Kelsey H. Collins, Yun-Rak Choi, Sara J. Oswald, View ORCID ProfileFarshid Guilak
doi: https://doi.org/10.1101/619239
Ruhang Tang
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USA
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Natalia S. Harasymowicz
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USA
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Chia-Lung Wu
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USA
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Kelsey H. Collins
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USA
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Yun-Rak Choi
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USADepartment of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, South Korea
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Sara J. Oswald
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USA
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Farshid Guilak
Department of Orthopaedic Surgery, Washington University St. Louis, MO, USAShriners Hospitals for Children – St. Louis, MO, USACenter of Regenerative Medicine, Washington University St. Louis, MO, USA
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  • ORCID record for Farshid Guilak
  • For correspondence: guilak@wustl.edu
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ABSTRACT

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Recent studies indicate that follistatin (FST), a protein which binds myostatin and activin, may have the potential to enhance muscle formation while neutralizing inflammation induced by these proteins. Here, we hypothesized that adeno-associated virus (AAV9) delivery of FST will enhance muscle formation and mitigate metabolic inflammation and knee OA caused by a high fat diet in mice. Obese mice receiving AAV-mediated FST delivery exhibited decreased inflammatory adipokines and cytokines systemically in the serum as well as locally in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. While obesity disrupted the mitochondrial oxidative phosphorylation (OXPHOS) system in adipocytes, gene therapy for FST restored the key proteins involved in mitochondrial biogenesis, such as PPARγ coactivator 1α and AKT protein kinase 1, leading to the browning of white adipose tissue. Taken together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

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Posted April 25, 2019.
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Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice
Ruhang Tang, Natalia S. Harasymowicz, Chia-Lung Wu, Kelsey H. Collins, Yun-Rak Choi, Sara J. Oswald, Farshid Guilak
bioRxiv 619239; doi: https://doi.org/10.1101/619239
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Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice
Ruhang Tang, Natalia S. Harasymowicz, Chia-Lung Wu, Kelsey H. Collins, Yun-Rak Choi, Sara J. Oswald, Farshid Guilak
bioRxiv 619239; doi: https://doi.org/10.1101/619239

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