Biology subjects

McGowan, L. M.

Publications and source records attributed to McGowan, L. M..

3 recordsLinked to original sources

bioRxiv2026

NSAIDs impair fracture healing by disrupting neutrophil-mediated repair

Neutrophils are among the first immune cells recruited to fractures, yet their contribution to bone repair remains poorly understood. Using live imaging and neutrophil perturbation in adult zebrafish, we show that neutrophils establish the early fracture microenvironment. Neutrophils rapidly accumulated at fractures, underwent NETosis, and exhibited transcriptional programmes associated with matrix remodelling. Compromising neutrophil recruitment, via ibuprofen treatment or orthogonal perturbations, increased fracture non-union, delayed osteoblast differentiation, impaired mineralisation, and altered callus architecture. Mechanistically, neutrophils actively interacted with extracellular matrix proteins, including laminin, fibronectin, and collagen I, through uptake, trafficking and secretion-associated pathways. Together, our findings reveal that neutrophils establish a provisional emergency fracture matrix that templates subsequent bone repair, providing a mechanistic link between early non-steroidal anti-inflammatory drug (NSAID) exposure and impaired skeletal regeneration.

immunology↗

bioRxiv2020

Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish

Bone homeostasis is a dynamic, multicellular process which is required throughout life to maintain bone integrity, prevent fracture and respond to skeletal damage. WNT16 has been linked to bone fragility and osteoporosis in humans, as well as functional haematopoiesis of leukocytes in vivo, but the mechanisms by which it promotes bone health and repair are not fully understood. We used CRISPR-Cas9 to generate mutant zebrafish lacking Wnt16 (wnt16-/-) to study its effect on bone dynamically. wnt16 mutants displayed variable tissue mineral density and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins of wnt16-/- and wild type (WT) zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell-dynamics in vivo. wnt16 mutants repaired fractures more slowly compared to WT zebrafish. Osteoblast cell number was reduced at the fracture site 4 days post-injury in wnt16 mutants, coinciding with prolonged activation of the canonical Wnt signalling pathway. Surprisingly, we found no evidence that the recruitment of innate immune cells to fractures was altered in wnt16 mutants. This study highlights zebrafish as an emerging model for functionally validating osteoporosis-associated genes and investigating fracture repair dynamically in vivo. Using this model, we demonstrate that Wnt16 protects against fracture and is likely to support bone repair by attenuating the activation of the canonical Wnt signalling pathway to facilitate osteoblast recruitment and bone matrix deposition.

cell biology↗

bioRxiv2018

Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers of autoimmune and atopic disease

Immune mediated diseases (IMDs) arise from a lack of immune tolerance, causing chronic inflammation. Despite their growing prevalence, targeted therapies to treat IMDs are lacking. Cytokines and their receptors, which mediate inflammation, have been associated with IMD susceptibility. However, the complex signalling networks and multiple cell-types required to orchestrate inflammatory responses have made it difficult to pinpoint specific cytokines and immune cell-types which drive IMDs.\n\nIn this study, we developed an analytical framework which integrates Mendelian randomisation (MR) and multiple-trait colocalization (moloc) analyses to determine putative cell-specific drivers of IMDs. We used MR to determine the likelihood of causal associations between the levels of 10 circulating cytokines/cytokine receptors and 9 IMDs within human populations of European descent. Conservative (single SNP) and liberal (multiple SNP) MR analysis supported a causal role for IL-18 in inflammatory bowel disease (P = 1.17 x 10-4) and eczema/dermatitis (P = 2.81 x 10-3), as well as roles for IL-2r and IL-6R in several IMDs.\n\nWhere associations between cytokines/cytokine receptors and IMDs were discovered using MR, we undertook moloc analyses. This was to assess the likelihood that cytokine/cytokine receptor protein quantitative trait loci (pQTL) and IMD-associated loci share a causal genetic variant along with expression QTL (eQTL) using data from 3 immune cell-types: monocytes, neutrophils and T cells. We found a monocyte and neutrophil-driven role for IL-18 in IBD pathogenesis, amongst evidence supporting several other cell-specific inflammatory drivers of IMDs. Our study helps to elucidate causal pathways for the pathogeneses of IMDs which, together with other studies, highlights possible therapeutic targets for their treatment.

genetics↗