title: Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish.
abstract: Paclitaxel is a microtubule-stabilizing chemotherapeutic agent that is widely used in cancer treatment and in a number of curative and palliative regimens. Despite its beneficial effects on cancer, paclitaxel also damages healthy tissues, most prominently the peripheral sensory nervous system. The mechanisms leading to paclitaxel-induced peripheral neuropathy remain elusive, and therapies that prevent or alleviate this condition are not available. We established a zebrafish in vivo model to study the underlying mechanisms and to identify pharmacological agents that may be developed into therapeutics. Both adult and larval zebrafish displayed signs of paclitaxel neurotoxicity, including sensory axon degeneration and the loss of touch response in the distal caudal fin. Intriguingly, studies in zebrafish larvae showed that paclitaxel rapidly promotes epithelial damage and decreased mechanical stress resistance of the skin before induction of axon degeneration. Moreover, injured paclitaxel-treated zebrafish skin and scratch-wounded human keratinocytes (HEK001) display reduced healing capacity. Epithelial damage correlated with rapid accumulation of fluorescein-conjugated paclitaxel in epidermal basal keratinocytes, but not axons, and up-regulation of matrix-metalloproteinase 13 (MMP-13, collagenase 3) in the skin. Pharmacological inhibition of MMP-13, in contrast, largely rescued paclitaxel-induced epithelial damage and neurotoxicity, whereas MMP-13 overexpression in zebrafish embryos rendered the skin vulnerable to injury under mechanical stress conditions. Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions.
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Elias
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Adriana D
authors.initials: AD
authors.lastname: Pellegrini
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Paige B
authors.initials: PB
authors.lastname: Martin
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Spaulding
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Olivia
authors.initials: O
authors.lastname: Lopes
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Brochu
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Erin V
authors.initials: EV
authors.lastname: Carter
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672.
authors.forename: Ashley
authors.initials: A
authors.lastname: Waldron
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Salisbury Cove, ME 04672 srieger@mdibl.org.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rieger
mesh_terms: D058500:Animal Fins / Q000166:cytology / Q000294:innervation; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001369:Axons / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects*; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D017239:Paclitaxel / Q000009:adverse effects*; D010525:Peripheral Nerves / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000294:innervation; D055698:Touch Perception / Q000187:drug effects; D018675:Toxicity Tests; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13; D017239:Paclitaxel
keywords: MMP-13; Taxol; degeneration; epidermis; regeneration