Matrix metalloproteinase inhibitor(ConjuChem/Servier)

Aquaporin-4 (AQP4) is a water channel that maintains cerebrospinal fluid homeostasis through polarized membrane localization and serves as a primary mediator for the clearance of neurotoxic metabolites within the central nervous system (CNS). The precise localization and functional stability of AQP4 rely on multiple regulatory processes, including transcriptional readthrough, interactions with cytoskeletal components, isoform assembly, and post-translational modifications. Disruption of these mechanisms leads to AQP4 depolarization, contributing to the pathogenesis of several neurological diseases including cerebrovascular diseases, neurodegenerative conditions, traumatic brain injury, and epilepsy. This review synthesizes current research advances on AQP4 localization and polarization, aiming to summarize its roles in normal physiology and disease pathogenesis. Preclinical findings in restoring AQP4 polarization, including pharmaceutical facilitator, matrix metalloproteinase inhibitor, repurposed drugs, hormone-based interventions, and stem cell/exosome therapies, underscore AQP4 polarization as a promising therapeutic target. To bridge the gap in clinical translation, we propose that future research should focus on investigating the deeper molecular mechanisms regulating AQP4 polarization and exploring clinically effective therapeutic approaches with high selectivity for CNS astrocytes.

Osteoarthritis (OA) is a prevalent joint disorder, characterized by cartilage degradation driven by matrix metalloproteinases (MMPs) and dysregulated extracellular matrix (ECM) turnover. Biological macromolecules, such as ECM-derived scaffolds, offer therapeutic potential by mimicking native cartilage composition, yet their rapid enzymatic breakdown hampers regenerative potential. We hypothesized that embedding an MMP inhibitor within ECM could mitigate MMP-driven breakdown, thereby halting OA progression, while stabilizing ECM structure and boosting chondrogenesis. Thus, we developed doxycycline-loaded micronized dehydrated human amniotic membrane (Dox-mdHAM), leveraging doxycycline as an MMP inhibitor, to regulate cartilage homeostasis in OA.

Dox-mdHAM was prepared by loading doxycycline onto human amniotic membrane, followed by dehydration and micronization. MMP activity and ECM content (collagen, glycosaminoglycans, growth factors) was assessed in Dox-mdHAM scaffolds. In vitro, C28/I2 human chondrocytes were cultured with Dox-mdHAM to assess cell morphology, chondrogenic marker expression, and TGFβ-1 levels. In vivo, Dox-mdHAM was injected intra-articularly in a monosodium iodoacetate-induced rat OA model to evaluate mobility, pain, and cartilage regeneration.

Dox-mdHAM characterization demonstrated reduced MMP-2 activity significantly, and enhanced ECM preservation with increased collagen and glycosaminoglycan content compared to untreated scaffolds. In vitro, Dox-mdHAM improved chondrogenic activity, notably upregulating expression of Collagen II, Aggrecan, and Sox9, while lowering TGFβ-1 levels. Moreover, in vivo, Dox-mdHAM supported cartilage regeneration with increased cartilage thickness and enhanced ECM deposition, while inhibiting degeneration, improving mobility and pain thresholds over time significantly.

Dox-mdHAM demonstrates a dual therapeutic action in OA by inhibiting cartilage degeneration through MMP suppression and TGFβ-1 reduction, while promoting regeneration via ECM preservation and enhanced chondrogenesis. These results underscore the potential of Dox-mdHAM in translational medicine as a promising disease-modifying therapy for OA.