---
title: "Constitutive PDGFRβ activation causes connective tissue overgrowth via STAT5–IGF1 signaling"
id: "biorxiv-26-constitutive-pdgfrb-activation-drives-connective-tissue-overgrowth-through"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-26-constitutive-pdgfrb-activation-drives-connective-tissue-overgrowth-through"
content_type: "clinical_feed_article"
specialty: "Endocrinology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.27.747555v1?rss=1"
published_at: "2026-08-29T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Constitutive PDGFRβ activation causes connective tissue overgrowth via STAT5–IGF1 signaling
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-26-constitutive-pdgfrb-activation-drives-connective-tissue-overgrowth-through
- **Specialty:** [Endocrinology](https://medichelpline.com/clinical-feed/endocrinology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.27.747555v1?rss=1)
- **Published At:** 2026-08-29T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Autosomal dominant gain-of-function mutations in **PDGFRβ** cause skeletal and connective tissue overgrowth in Kosaki overgrowth syndrome; the responsible target cell type and downstream signaling had been unclear. - The authors generated mice carrying a PDGFRβ gain-of-function mutation targeted to **skeletal and fibroblast lineages**, producing STAT5 activation and a **gigantism** phenotype. - Conditional deletion of **Stat5ab** in connective tissue lineages reversed skeletal overgrowth and resolved keloid-like skin fibrosis, indicating STAT5 is required for the overgrowth phenotype. - Conditional deletion of the **growth hormone receptor (Ghr)** did not prevent overgrowth, showing that the canonical pituitary **GH → STAT5** physiological activator is not necessary for PDGFRβ-driven overgrowth. - Targeted deletion of **Igf1** and of its receptor **Igf1r** in connective tissue also rescued the overgrowth phenotype, identifying IGF1 as an essential STAT5 target mediating PDGFRβ effects. - Together, the data support a **GHR-independent STAT5–IGF1 signaling pathway** operating within mutant connective tissue cells that drives PDGFRβ-mediated overgrowth in mice and may be relevant to humans with similar PDGFRB mutations. - The study reports no competing interests and lists support from NIH institutes and regional foundations; specific experimental details and quantitative metrics beyond the reported genetic manipulations and phenotypes were not included in the source summary.
## Clinical Analysis & Structured Key Points
Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling | bioRxiv Skip to main content New Results Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling Hae Ryong Kwon , Alex Rackley , View ORCID Profile Lorin E. Olson doi: https://doi.org/10.64898/2026.08.27.747555 Hae Ryong Kwon Oklahoma Medical Research Foundation Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alex Rackley Oklahoma Medical Research Foundation Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lorin E. Olson Oklahoma Medical Research Foundation Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lorin E. Olson For correspondence: lorin-olson{at}omrf.org Abstract Info/History Metrics Preview PDF Abstract Autosomal dominant gain-of-function mutations in platelet-derived growth factor receptor beta (PDGFRb) cause overgrowth of the skeleton and other connective tissue in Kosaki overgrowth syndrome. However, the target cell type and signaling pathways underlying PDGFRb-driven overgrowth are unknown. Normal postnatal growth is controlled by pituitary-secreted growth hormone (GH), which activates the STAT5 transcriptional factor to upregulate insulin-like growth factor 1 (IGF1). To investigate the role of the GH-STAT5-IGF1 pathway in PDGFRb-related overgrowth, we generated mice with a PDGFRb gain-of-function mutation in skeletal and fibroblast lineages, which resulted in STAT5 activation and gigantism. Conditional deletion of Stat5ab in connective tissue lineages rescued skeletal overgrowth and keloid-like fibrosis in the skin. Conditional deletion of GH receptor (Ghr) did not rescue overgrowth, indicating the physiological activator of STAT5 is not required for overgrowth. However, deletion of Igf1, the STAT5 target gene, and its receptor, Igf1r, in connective tissue, rescued the overgrowth phenotype. These findings demonstrate a GHR-independent STAT5-IGF1 signaling pathway in mutant connective tissue cells, which mediates PDGFRb-driven overgrowth in mice and potentially in humans with similar PDGFRB mutations. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared National Heart Lung and Blood Institute , F32-HL142222 National Institute of Arthritis and Musculoskeletal and Skin Diseases , R01-AR073828 , R01-AR080896 Presbyterian Health Foundation, https://ror.org/01nbasn20 Oklahoma Center for Adult Stem Cell Research Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Back to top Previous Next Posted August 29, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling Hae Ryong Kwon , Alex Rackley , Lorin E. Olson bioRxiv 2026.08.27.747555; doi: https://doi.org/10.64898/2026.08.27.747555 Share This Article: Copy Citation Tools Constitutive PDGFRb activation drives connective tissue overgrowth through STAT5-IGF1 signaling Hae Ryong Kwon , Alex Rackley , Lorin E. Olson bioRxiv 2026.08.27.747555; doi: https://doi.org/10.64898/2026.08.27.747555 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Genetics Subject Areas All Articles Animal Behavior and Cognition (7945) Biochemistry (18565) Bioengineering (14718) Bioinformatics (43981) Biophysics (22375) Cancer Biology (19499) Cell Biology (26670) Clinical Trials (138) Developmental Biology (13855) Ecology (20805) Epidemiology (2067) Evolutionary Biology (25250) Genetics (16067) Genomics (23351) Immunology (18528) Microbiology (42092) Molecular Biology (17885) Neuroscience (92579) Paleontology (691) Pathology (2958) Pharmacology and Toxicology (5051) Physiology (8029) Plant Biology (15846) Scientific Communication and Education (2090) Synthetic Biology (4523) Systems Biology (10156) Zoology (2368)
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