GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury-Reference-Cited by-同舟云学术

GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury

Published:2023-12 Issue:48 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Brightwell Camille R.¹²^ORCID,Latham Christine M.¹²^ORCID,Keeble Alexander R.¹²,Thomas Nicholas T.¹²^ORCID,Owen Allison M.¹²^ORCID,Reeves Kelsey A.³,Long Douglas E.¹,Patrick Matthew⁴^ORCID,Gonzalez-Velez Sara¹^ORCID,Abed Varag⁵^ORCID,Annamalai Ramkumar T.⁴^ORCID,Jacobs Cale⁵^ORCID,Conley Caitlin E.⁵^ORCID,Hawk Gregory S.⁶^ORCID,Stone Austin V.⁵,Fry Jean L.¹²^ORCID,Thompson Katherine L.⁶,Johnson Darren L.⁵,Noehren Brian¹³⁵,Fry Christopher S.¹²^ORCID

Affiliation:

1. Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.

2. Department of Athletic Training and Clinical Nutrition, College of Health Sciences, University of Kentucky, Lexington, KY, USA.

3. Department of Physical Therapy, College of Health Sciences, University of Kentucky, Lexington, KY, USA.

4. Department of Biomedical Engineering, College of Engineering, University of Kentucky, Lexington, KY, USA.

5. Department of Orthopaedic Surgery and Sports Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA.

6. Department of Statistics, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA.

Abstract

Musculoskeletal disorders contribute substantially to worldwide disability. Anterior cruciate ligament (ACL) tears result in unresolved muscle weakness and posttraumatic osteoarthritis (PTOA). Growth differentiation factor 8 (GDF8) has been implicated in the pathogenesis of musculoskeletal degeneration following ACL injury. We investigated GDF8 levels in ACL-injured human skeletal muscle and serum and tested a humanized monoclonal GDF8 antibody against a placebo in a mouse model of PTOA (surgically induced ACL tear). In patients, muscle GDF8 was predictive of atrophy, weakness, and periarticular bone loss 6 months following surgical ACL reconstruction. In mice, GDF8 antibody administration substantially mitigated muscle atrophy, weakness, and fibrosis. GDF8 antibody treatment rescued the skeletal muscle and articular cartilage transcriptomic response to ACL injury and attenuated PTOA severity and deficits in periarticular bone microarchitecture. Furthermore, GDF8 genetic deletion neutralized musculoskeletal deficits in response to ACL injury. Our findings support an opportunity for rapid targeting of GDF8 to enhance functional musculoskeletal recovery and mitigate the severity of PTOA after injury.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adi9134

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