Otto, E. | bioRxiv Science

bioRxiv2023

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/548550v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@cea57corg.highwire.dtl.DTLVardef@d29642org.highwire.dtl.DTLVardef@186ea5aorg.highwire.dtl.DTLVardef@83eaae_HPS_FORMAT_FIGEXP M_FIG Artwork was created in BioRender. C_FIG

cell biology↗

bioRxiv2018

An eQTL landscape of kidney tissue in human nephrotic syndrome

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTLs studies of human kidney. Here, we used whole genome sequencing (WGS) and microdissected glomerular (GLOM) & tubulointerstitial (TI) transcriptomes from 187 patients with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures.\n\nUsing MatrixEQTL, we performed cis-eQTL analysis on GLOM (n=136) and TI (n=166). We used the Bayesian \"Deterministic Approximation of Posteriors\" (DAP) to fine-map these signals, eQtlBma to discover GLOM-or TI-specific eQTLs, and single cell RNA-Seq data of control kidney tissue to identify cell-type specificity of significant eQTLs. We integrated eQTL data with an IgA Nephropathy (IGAN) GWAS to perform a transcriptome-wide association study (TWAS).\n\nWe discovered 894 GLOM eQTLs and 1767 TI eQTLs at FDR <0.05. 14% and 19% of GLOM & TI eQTLs, respectively, had > 1 independent signal associated with its expression. 12% and 26% of eQTLs were GLOM-specific and TI-specific, respectively. GLOM eQTLs were most significantly enriched in podocyte transcripts and TI eQTLs in proximal tubules. The IGAN TWAS identified significant GLOM & TI genes, primarily at the HLA region.\n\nIn this study of NS patients, we discovered GLOM & TI eQTLs, identified those that were tissue-specific, deconvoluted them into cell-specific signals, and used them to characterize known GWAS alleles. These data are publicly available for browsing and download at http://nephqtl.org.

genomics↗