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journal article·2026-07-09Open access

Kaempferol Attenuates Spaceflight‐Associated Knee Cartilage Degradation by Targeting NOX4‐Mediated Mitochondrial Dysfunction

Yuesong Yin, Ruiling Xu, Meagan J. Makarczyk, Jia‐Jun Liu, Silvia Liu, Matthew Z. Shi, Roberta Di Carlo, Michael F. Almeida, Alex Garris, Sarah Day, Rebekah Sanchez‐Hodge, Jonathan C. Schisler, Aleeza H. Zilberman, Noah G. Allen, Angela J. Kubik, Elizabeth A. Blaber, Arnold Z. Olali, Wanqing Xie, Douglas C. Wallace, Christopher E. Mason, Peter G. Alexander, Giuseppe Intini, Afshin Beheshti, Hang Lin

Advanced Science
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Abstract

ABSTRACT Microgravity and space radiation experienced during spaceflight have adverse effects on musculoskeletal health, yet their impact on articular cartilage has not been fully understood. In this study, we demonstrated that simulated spaceflight on Earth leads to cartilage degradation in the knees of mice. Similar changes were also observed in mice exposed to actual spaceflight. To investigate mechanisms underlying spaceflight‐associated cartilage loss, human chondrocytes were encapsulated in a hydrogel scaffold and subjected to rotary culture to simulate microgravity‐induced alterations. Simulated microgravity increased the expression of biomarkers related to inflammation and cellular senescence. Additionally, rotary culture decreased mitochondrial respiration and increased reactive oxygen species production. Through RNA sequencing and bioenergetic profiling, we identified NADPH oxidase 4 (NOX4) as a crucial factor driving these changes. Moreover, kaempferol, a naturally occurring flavonoid that directly binds to NOX4, was found to partially reverse the harmful effects of microgravity on chondrocytes. Finally, systemic administration of kaempferol reduced cartilage degradation in mice subjected to simulated spaceflight on the ground. These findings establish that NOX4‐mediated mitochondrial dysfunction is a key mechanism underlying spaceflight‐induced cartilage degradation and highlight kaempferol as a potential protective measure for joint health in space.
Source: crossref · Quality: baseline

Research context

Polymers

OpenAlex topics: Spaceflight effects on biology · Muscle Physiology and Disorders · High Altitude and Hypoxia

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Orthopaedic Surgery University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Department of Bioengineering University of Pittsburgh Swanson School of Engineering Pittsburgh Pennsylvania USA

Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Organ Pathobiology and Therapeutics Institute University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Department of Periodontics and Preventive Dentistry University of Pittsburgh School of Dental Medicine Pittsburgh Pennsylvania USA

Center For Craniofacial Regeneration University of Pittsburgh School of Dental Medicine Pittsburgh Pennsylvania USA

McAllister Heart Institute and Department of Pharmacology The University of North Carolina At Chapel Hill Chapel Hill North Carolina USA

Shirley Ann Jackson Ph.D. Center for Biotechnology and Interdisciplinary Studies and Department of Biomedical Engineering Rensselaer Polytechnic Institute Troy New York USA

Center For Mitochondrial and Epigenomic Medicine The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

The Division of Human Genetics The Department of Pediatrics The Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Physiology and Biophysics Weill Cornell Medicine New York New York USA

Orland Bethel Family Musculoskeletal Research Center University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

University of Pittsburgh UPMC Hillman Cancer Center Pittsburgh Pennsylvania USA

Center For Space Biomedicine University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

McGowan Institute for Regenerative Medicine University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Department of Surgery University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Department of Computational and Systems Biology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania USA

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge Massachusetts USA

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