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Simulated microgravity models sex differences in knee osteoarthritis through a CD36-regulated mechano-metabolic circuit

ABSTRACT: Leveraging the unique conditions of space microgravity, our research offers groundbreaking insights into osteoarthritis (OA), a degenerative joint disease impacting over three million Canadians and predominantly affecting load-bearing joints such as the knee. With knee OA (KOA) known for its higher incidence and severity among females—a phenomenon not fully explained by existing risk factors—the application of simulated microgravity (SMG) presents a novel approach to understanding the disease's progression and the biological sex differences in response to it. By employing rotating wall vessel (RWV) technology to simulate spaceflight conditions on Earth, our studies focus on the biomechanical unloading experienced in microgravity, which has been observed to induce OA-like changes in articular tissues. This innovative research strategy allows us to explore the potential mechanisms of OA development and progression in a controlled environment, mimicking the microgravity of space to provide new perspectives on the disease's molecular underpinnings. Initial results from our investigations reveal that SMG significantly alters the molecular expression profiles in engineered meniscus constructs derived from non-KOA patients, notably influencing genes related to chondrocyte hypertrophy and OA progression while downregulating protective genes. Further analysis has illuminated sex-specific molecular responses to SMG, demonstrating pronounced differences between male and female specimens. This highlights the importance of considering biological sex in OA research, as it significantly influences disease development and response to microgravity conditions. Extended RNA sequencing under SMG conditions has identified distinct molecular signatures for different sex-based groups, pointing towards an OA-like transcriptome profile in females particularly responsive to SMG. One of the most significant findings from our microgravity studies is the modulation of CD36, a transmembrane protein implicated in lipid metabolism and OA pathogenesis. Its altered expression under SMG conditions and known upregulation in KOA patients underscore the potential mechanisms by which microgravity-induced cellular responses can mimic and inform us about OA development, particularly in terms of sex-specific disparities.

ORGANISM(S): Mus musculus

PROVIDER: GSE300617 | GEO | 2026/04/05

REPOSITORIES: GEO

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Project description:Gravitational biology and its effects on cancer cells are of great interest, especially today that space is more accessible than ever. Despite advances in space research, little is known about the impact of microgravity on tumor and its biology and data from the literature are often contradictory due to different setup, experimental designs and analyzed time-points. Exploiting the Random Positioning machine we evaluated on pancreatic cancer cells the effects of long-term exposure to simulated microgravity (SMG) performing a large proteomic, lipidomic and transcriptional analysis at 1, 7 and 9 days. Results indicate that SMG affects cellular morphology through a time-dependent activation of “Regulation of actin-based motility by Rho”and “Cdc42” pathways that contribute to the dynamic actin rearrangement involved in the formation of 3D spheroidal structures and in the enhancement of epithelial-to mesenchymal transition. To support energy stress remediation and counteract massive apoptosis activation and cell proliferation inhibition, induced by SMG, tumor cells downregulate the protein translational machinery, and undergo a metabolic reprogramming orchestrated by the activation of HIF-1a and PI3K/Akt pathways. These two pathways pave the way for glucose metabolism encouraging upregulation of glycolysis, mitochondrial activity, Tri-carboxylic acid cycle and fatty acid synthesis (rather than B oxidation), suggesting a de novo synthesis of triglycerides involved in the formation of membrane lipid bilayer and signaling mediators. This metabolic plasticity, typical of cancer stem cells, is in accordance with the SMG-mediated activation of PI3K/Akt/NFkB/ERK5/IL-8 signaling axis that significantly upregulates the expression of stem-associated proteins and expansion of cancer stem cells with a more mesenchymal phenotype and improved migratory capability. Altogether, our findings clearly indicate that microgravity induces cancer cell transformation towards the acquisition of cancer stem cell-like features, with a more aggressive and metastatic potential and pave the base for future study of response to anti neoplastic drugs under simulated microgravity.

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Simulated microgravity models sex differences in knee osteoarthritis through a CD36-regulated mechano-metabolic circuit

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