TY - JOUR
T1 - GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury
AU - Brightwell, Camille R.
AU - Latham, Christine M.
AU - Keeble, Alexander R.
AU - Thomas, Nicholas T.
AU - Owen, Allison M.
AU - Reeves, Kelsey A.
AU - Long, Douglas E.
AU - Patrick, Matthew
AU - Gonzalez-Velez, Sara
AU - Abed, Varag
AU - Annamalai, Ramkumar T.
AU - Jacobs, Cale
AU - Conley, Caitlin E.
AU - Hawk, Gregory S.
AU - Stone, Austin V.
AU - Fry, Jean L.
AU - Thompson, Katherine L.
AU - Johnson, Darren L.
AU - Noehren, Brian
AU - Fry, Christopher S.
N1 - Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85178202319
U2 - 10.1126/SCIADV.ADI9134
DO - 10.1126/SCIADV.ADI9134
M3 - Article
C2 - 38019905
AN - SCOPUS:85178202319
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 48
M1 - eadi9134
ER -