Autosomal dominant activating mutations in platelet-derived growth factor receptor beta (PDGFRβ) are linked to connective tissue and skeletal overgrowth, exemplified by Kosaki overgrowth syndrome. Prior to this report, the specific connective tissue target cell types and the intracellular signaling cascade mediating PDGFRβ-driven overgrowth were not defined. Normal postnatal somatic growth is regulated by pituitary-derived growth hormone (GH), which classically activates the transcription factor STAT5 to induce expression of insulin-like growth factor 1 (IGF1). Whether PDGFRβ-driven overgrowth co-opts this endocrine GH–STAT5–IGF1 axis or engages a distinct, cell-intrinsic pathway was unknown.
To investigate the downstream mediators of PDGFRβ-driven tissue overgrowth, the investigators generated mice bearing a constitutive PDGFRβ gain-of-function mutation targeted to skeletal and fibroblast lineages. In these animals, the PDGFRβ mutation produced activation of STAT5 and a pronounced gigantism phenotype. The source summary does not provide detailed methods, quantitative growth measures, or histologic protocols; those experimental specifics were not reported in the source text.
The authors tested the requirement for STAT5 by conditionally deleting the Stat5ab locus in the same connective tissue lineages that expressed the PDGFRβ gain-of-function allele. Conditional deletion of Stat5ab rescued skeletal overgrowth and reversed keloid-like fibrosis in the skin. These results indicate that STAT5 activation in mutant connective tissue cells is necessary for the PDGFRβ-driven overgrowth phenotype observed in the mouse model.
Because STAT5 is a canonical effector of pituitary GH signaling, the study examined whether physiological GH input via the growth hormone receptor (GHR) is required for the overgrowth. Conditional deletion of Ghr in the relevant connective tissue lineages did not rescue the overgrowth phenotype, indicating that the canonical endocrine activator of STAT5 is not necessary for PDGFRβ-induced growth. This result supports a model in which STAT5 activation occurs in a GHR-independent manner downstream of mutant PDGFRβ within connective tissue cells.
To determine whether IGF1, a transcriptional target of STAT5, mediates the downstream effects of STAT5 in this context, the investigators conditionally deleted Igf1 and separately deleted its receptor Igf1r in connective tissue lineages carrying the PDGFRβ mutation. Deletion of either Igf1 or Igf1r rescued the overgrowth phenotype. These findings place IGF1 signaling downstream of STAT5 as a necessary mediator of PDGFRβ-driven connective tissue and skeletal overgrowth in the mouse model.
Collectively, the genetic epistasis experiments reported in the source support a pathway in which constitutively active PDGFRβ in connective tissue cells leads to activation of STAT5, which in turn drives expression of IGF1; IGF1 acting via IGF1R on connective tissue cells mediates the overgrowth and fibrotic skin changes. Because conditional deletion of Ghr did not block the phenotype, the pathway operates independently of pituitary-derived GH as the physiological STAT5 activator. The authors conclude that a cell-autonomous, GHR-independent STAT5–IGF1 signaling axis in mutant connective tissue cells underlies PDGFRβ-driven overgrowth in mice.
These mouse genetic data suggest that PDGFRB gain-of-function mutations in humans could promote tissue overgrowth through a similar cell-autonomous STAT5–IGF1 program independent of systemic GH. If conserved in humans, this mechanism could inform molecular diagnostics and the conceptual basis for targeting downstream signaling nodes (STAT5 or IGF1 signaling) rather than upstream endocrine regulators. The source summary does not report clinical trials, therapeutic interventions, or human patient data; translational relevance is presented as a potential implication rather than an experimentally demonstrated human finding.
The authors declared no competing interests. Funding sources listed include the National Heart, Lung, and Blood Institute (F32-HL142222), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR073828, R01-AR080896), the Presbyterian Health Foundation, and the Oklahoma Center for Adult Stem Cell Research. The source article summary does not include detailed numerical results, statistical analyses, experimental timelines, or procedural details; those specifics were not reported in the provided text.