ANTXR2 Deficiency Promotes Cellular Senescence and Chondroid Differentiation in Hyaline Fibromatosis Syndrome Fibroblasts

Mutations in anthrax toxin receptor 2 (ANTXR2) cause hyaline fibromatosis syndrome (HFS), a rare genetic disorder marked by subcutaneous nodules filled with amorphous hyaline extracellular material. In addition to these nodules, HFS patients exhibit gingival hypertrophy, joint contractures, osteolytic lesions, and, in severe cases, intractable diarrhea. The mechanisms by which ANTXR2 regulates extracellular matrix (ECM) composition and connective tissue homeostasis remain incompletely understood. Here, we show that dermal fibroblasts from HFS patients exhibit hallmarks of cellular senescence, chondroid differentiation and abnormal ECM deposition. Additionally, HFS dermal fibroblasts are refractory to matrix metalloproteinase (MMP) 2 and 9 activation, potentially explaining phenotypic similarities between HFS and disorders caused by loss-of-function mutations in MMP genes. These findings underscore the essential role of ANTXR2 in maintaining dermal fibroblast identity and connective tissue homeostasis, laying the groundwork for novel therapeutic interventions for HFS. RNA-seq profiling of primary human dermal fibroblasts from a healthy donor (CTRL #1), a Hyaline Fibromatosis Syndrome (HFS) patient (HFS #1), and a second healthy donor transfected with either a non-targeting control siRNA (siCTRL) or two independent siRNAs targeting ANTXR2 (siANTXR2_a and siANTXR2_b). All conditions were performed in biological triplicates.