GDF8 Inhibition Enhances Musculoskeletal Recovery and Mitigates Posttraumatic Osteoarthritis Following Joint Injury

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2023 Nov 29

PMID 38019905

Authors

Camille R Brightwell

Christine M Latham

Alexander R Keeble

Nicholas T Thomas

Allison M Owen

Kelsey A Reeves

Douglas E Long

Matthew Patrick

Sara Gonzalez-Velez

Varag Abed

Ramkumar T Annamalai

Cale Jacobs

Caitlin E Conley

Gregory S Hawk

Austin V Stone

Jean L Fry

Katherine L Thompson

Darren L Johnson

Brian Noehren

Christopher S Fry

Affiliations

Soon will be listed here.

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.

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