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

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

doi:10.1126/sciadv.adi9134

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

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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Pages (from-to)	eadi9134
Journal	Science advances
Volume	9
Issue number	48
DOIs	https://doi.org/10.1126/sciadv.adi9134
State	Published - Dec 2023

Keywords

Animals
Humans
Mice
Anterior Cruciate Ligament Injuries/complications
Disease Models, Animal
Muscle, Skeletal/pathology
Myostatin/genetics
Osteoarthritis/drug therapy

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10.1126/sciadv.adi9134

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Brightwell, C. R., Latham, C. M., Keeble, A. R., Thomas, N. T., Owen, A. M., Reeves, K. A., Long, D. E., Patrick, M., Gonzalez-Velez, S., Abed, V., Annamalai, R. T., Jacobs, C., Conley, C. E., Hawk, G. S., Stone, A. V., Fry, J. L., Thompson, K. L., Johnson, D. L., Noehren, B., & Fry, C. S. (2023). GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury. Science advances, 9(48), eadi9134. https://doi.org/10.1126/sciadv.adi9134

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title = "GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury",

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.",

keywords = "Animals, Humans, Mice, Anterior Cruciate Ligament Injuries/complications, Disease Models, Animal, Muscle, Skeletal/pathology, Myostatin/genetics, Osteoarthritis/drug therapy",

author = "Brightwell, {Camille R} and Latham, {Christine M} and Keeble, {Alexander R} and Thomas, {Nicholas T} and Owen, {Allison M} and Reeves, {Kelsey A} and Long, {Douglas E} and Matthew Patrick and Sara Gonzalez-Velez and Varag Abed and Annamalai, {Ramkumar T} and Cale Jacobs and Conley, {Caitlin E} and Hawk, {Gregory S} and Stone, {Austin V} and Fry, {Jean L} and Thompson, {Katherine L} and Johnson, {Darren L} and Brian Noehren and Fry, {Christopher S}",

year = "2023",

month = dec,

doi = "10.1126/sciadv.adi9134",

language = "English",

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Brightwell, CR, Latham, CM, Keeble, AR, Thomas, NT, Owen, AM, Reeves, KA, Long, DE, Patrick, M, Gonzalez-Velez, S, Abed, V, Annamalai, RT, Jacobs, C , Conley, CE , Hawk, GS , Stone, AV , Fry, JL , Thompson, KL , Johnson, DL , Noehren, B & Fry, CS 2023, 'GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury', Science advances, vol. 9, no. 48, pp. eadi9134. https://doi.org/10.1126/sciadv.adi9134

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

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.

KW - Animals

KW - Humans

KW - Mice

KW - Anterior Cruciate Ligament Injuries/complications

KW - Disease Models, Animal

KW - Muscle, Skeletal/pathology

KW - Myostatin/genetics

KW - Osteoarthritis/drug therapy

U2 - 10.1126/sciadv.adi9134

DO - 10.1126/sciadv.adi9134

M3 - Article

C2 - 38019905

VL - 9

SP - eadi9134

JO - Science advances

JF - Science advances

IS - 48

ER -

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

Abstract

Keywords

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