GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.
Camille R BrightwellChristine M LathamAlexander R KeebleNicholas T ThomasAllison M OwenKelsey A ReevesDouglas E LongMatthew PatrickSara Gonzalez-VelezVarag AbedRamkumar T AnnamalaiCale A JacobsCaitlin E W ConleyGregory S HawkAustin V StoneJean L FryKatherine L ThompsonDarren L JohnsonBrian NoehrenChristopher S FryPublished in: Science advances (2023)
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.
Keyphrases
- skeletal muscle
- bone loss
- mouse model
- insulin resistance
- traumatic brain injury
- multiple sclerosis
- endothelial cells
- end stage renal disease
- knee osteoarthritis
- genome wide
- clinical trial
- metabolic syndrome
- oxidative stress
- single cell
- radiation therapy
- bone mineral density
- adipose tissue
- body composition
- diabetic rats
- prognostic factors
- high fat diet induced
- cancer therapy
- induced pluripotent stem cells
- open label
- pluripotent stem cells
- liver fibrosis