GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.
GDF8 inhibition enhances musculoskeletal recovery and mitigates posttraumatic osteoarthritis following joint injury.
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DOI：
10.1126/sciadv.adi9134
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发表时间：
2023-12
期刊：
影响因子：
13.6
通讯作者：
Fry, Christopher S.
中科院分区：
文献类型：
--
作者：
Brightwell, Camille R.;Latham, Christine M.;Keeble, Alexander R.;Thomas, Nicholas T.;Owen, Allison M.;Reeves, Kelsey A.;Long, Douglas E.;Patrick, Matthew;Gonzalez-Velez, Sara;Abed, Varag;Annamalai, Ramkumar T.;Jacobs, Cale;Conley, Caitlin E.;Hawk, Gregory S.;Stone, Austin V.;Fry, Jean L.;Thompson, Katherine L.;Johnson, Darren L.;Noehren, Brian;Fry, Christopher S.
肌肉骨骼疾病在很大程度上造成了全世界的残疾。前交叉韧带（ACL）撕裂导致未解决的肌无力和创伤后骨关节炎（PTOA）。生长分化因子8（GDF 8）与ACL损伤后肌肉骨骼退化的发病机制有关。我们研究了ACL损伤的人骨骼肌和血清中的GDF8水平，并在PTOA（手术诱导的ACL撕裂）小鼠模型中测试了针对安慰剂的人源化单克隆GDF8抗体。在患者中，肌肉GDF8可预测ACL重建手术后6个月的萎缩、虚弱和关节周围骨丢失。在小鼠中，GDF8抗体施用基本上减轻了肌肉萎缩、虚弱和纤维化。GDF8抗体治疗挽救了骨骼肌和关节软骨对ACL损伤的转录组反应，并减轻了PTOA严重程度和关节周围骨微结构的缺陷。此外，GDF8基因缺失中和了ACL损伤引起的肌肉骨骼缺陷。我们的研究结果支持快速靶向GDF8以增强功能性肌肉骨骼恢复并减轻损伤后PTOA的严重程度的机会。阻断生长分化因子8减轻创伤后骨关节炎进行性肌肉骨骼退化。
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. Blockade of growth differentiation factor 8 abates progressive musculoskeletal degeneration in posttraumatic osteoarthritis.
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影响因子：
4.9
作者：
Attur M;Duan X;Cai L;Han T;Zhang W;Tycksen ED;Samuels J;Brophy RH;Abramson SB;Rai MF
通讯作者：
Rai MF
影响因子：
8
作者：
Brightwell CR;Kulkarni AS;Paredes W;Zhang K;Perkins JB;Gatlin KJ;Custodio M;Farooq H;Zaidi B;Pai R;Buttar RS;Tang Y;Melamed ML;Hostetter TH;Pessin JE;Hawkins M;Fry CS;Abramowitz MK
通讯作者：
Abramowitz MK
DOI：
10.1002/jor.23537
发表时间：
2017-11
期刊：
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
影响因子：
--
作者：
Wurtzel CN;Gumucio JP;Grekin JA;Khouri RK Jr;Russell AJ;Bedi A;Mendias CL
通讯作者：
Mendias CL
影响因子：
8
作者：
Hammers, David W.;Hart, Cora C.;Sweeney, H. Lee
通讯作者：
Sweeney, H. Lee
影响因子：
14
作者：
Annamalai, Ramkumar T.;Hong, Xiaowei;Stegemann, Jan P.
通讯作者：
Stegemann, Jan P.