Aberrant Mechano-Oxygen Coupling as a Driver of Zinc-Enriched Ectopic Mineralization in Osteoarthritis

About This Grant

ABSTRACT Interfaces are nature’s engineering solutions for connecting tissues with distinct mechanical and chemical properties to maintain joint function. When exposed to aberrant mechanical loads, the finely tuned equilibrium between cartilage and bone in load-bearing joints is disrupted, triggering oxidative stress and angiogenesis. This mechano-oxygen coupling is mediated by mechanosensitive ion channels, hypoxia-inducible signaling, and oxidative stress responses. Under pathological loading, these finely tuned pathways are altered, leading to a disruption of metabolism at the cartilage–bone interface. Notably, accumulation of zinc (Zn)-enriched minerals has emerged as a hallmark of abnormal mechanical stress. Elevated Zn levels also correlate with increased oxidative stress and endothelial cell activation across human, animal, and engineered systems, suggesting that Zn plays a key role in force- and oxygen-dependent mineralization. We therefore hypothesize that aberrant mechano-oxygen coupling induces pathological HIF-1α activation and angiogenesis, disrupts Zn homeostasis and cartilage metabolism, and drives Zn-enriched ectopic mineralization. To test this, we propose two aims: Aim 1: Correlate force-induced angiogenesis with biomineralization using an animal model; Aim 2: Elucidate the role of mechanical stress and cellular oxygen levels in mineralization using a bioengineered organoid model. This work integrates complementary expertise: Dr. Ho will conduct longitudinal studies in rats with overloaded temporomandibular joints (TMJ) and perform multimodal microspectroscopy of Zn-species; Dr. Komatsu will develop multicellular organoid and microfluidic systems to study crosstalk between chondrocytes, osteoblasts, and vascular endothelial cells; and Dr. Fahrni will perform bioanalytical assays to assess Zn levels, activity, proteome, and ligands in TMJ tissues and organoids. Together, this bioanalytical and bioengineering framework will reveal how the finely tuned mechano-oxygen gradients converge at the cartilage–bone interface to drive Zn- enriched ectopic mineralization in the TMJ. These insights will uncover how disruption of this tuned equilibrium contributes to TMJ osteoarthritis, enabling early biomarker discovery and strategies for precise diagnosis and intervention.