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GDF8 抑制可增强肌肉骨骼的恢复，并减轻关节损伤后的创伤性骨关节炎。

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

机构信息

Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.

Department of Athletic Training and Clinical Nutrition, College of Health Sciences, University of Kentucky, Lexington, KY, USA.

出版信息

Sci Adv. 2023 Dec;9(48):eadi9134. doi: 10.1126/sciadv.adi9134. Epub 2023 Nov 29.

DOI:10.1126/sciadv.adi9134
PMID:38019905
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10686569/
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.

摘要

肌肉骨骼疾病在全球范围内造成了大量残疾。前交叉韧带（ACL）撕裂导致肌肉无力和创伤后骨关节炎（PTOA）无法解决。生长分化因子 8（GDF8）已被牵连到 ACL 损伤后肌肉骨骼退化的发病机制中。我们研究了 ACL 损伤后人类骨骼肌和血清中的 GDF8 水平，并在 PTOA 小鼠模型（手术诱导的 ACL 撕裂）中测试了一种针对安慰剂的人源化单克隆 GDF8 抗体。在患者中，肌肉 GDF8 可预测术后 6 个月时的萎缩、无力和关节周围骨丢失。在小鼠中，GDF8 抗体给药可显著减轻肌肉萎缩、无力和纤维化。GDF8 抗体治疗挽救了 ACL 损伤后骨骼肌和关节软骨的转录组反应，并减轻了 PTOA 的严重程度和关节周围骨微结构的缺陷。此外，GDF8 基因缺失消除了 ACL 损伤后肌肉骨骼缺陷。我们的发现支持快速靶向 GDF8 的机会，以增强功能性肌肉骨骼恢复并减轻损伤后 PTOA 的严重程度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3497/10686569/693240c4f688/sciadv.adi9134-f7.jpg
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