Multiscale mechano-metabolic regulation of fibrous tissue homeostasis

ABSTRACT Meniscus tears are one of the most common knee injuries and often fail to heal in adults. Current surgical treatments increase osteoarthritis (OA) risk, especially in patients with metabolic syndrome (including obesity, hyperglycemia, and dyslipidemia). While this is often attributed to mechanical overloading, metabolic syndrome is also associated with OA in non-weightbearing joints. Preclinical studies suggest elevated inflammatory signals from adipose tissue (e.g., adipokine dysregulation) mediate articular cartilage degeneration following meniscal injury. Obesity and OA are associated with aberrant microstructural remodeling and strain attenuation in the outer meniscus. Despite these findings, the mechano-metabolic mechanisms controlling meniscus cell function remain unresolved. To address these gaps in knowledge, this proposal will investigate the impact of metabolic syndrome on meniscus cell mechanoactivation. Our central hypothesis is that persistent adipokine dysregulation exacerbates degeneration by altering meniscus cell setpoints for mechano-responsivity and perturbing their response to homeostatic signals. To test this hypothesis, this proposal uses novel, multiscale experimental techniques to determine if metabolic syndrome impairs transmission of tensional cues in the meniscus. Specifically, Aim 1 will test if mechano-metabolic interactions alter meniscus cell contractile force generation and response to static and dynamic microenvironmental cues. Aim 2 will determine how metabolic memory arising from transient and sustained adipokine dysregulation influences meniscus cell mechanoactivation, phenotype, and multiscale tissue mechanical properties in response to homeostatic and pathological tensional cues. I hypothesize that adipokine dysregulation will impair meniscus cell contractile force generation and mechanoactivation, leading to loss of fibrous phenotype and aberrant matrix remodeling. This work will generate novel insight into how mechanotransductive and metabolic crosstalk regulates fibrous tissue homeostasis and direct regenerative strategies for meniscus repair in high-risk patients.