Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice

Abstract
Multiple hereditary exostoses (MHE) is marked by the formation of numerous benign bony tumors called osteochondromas. Although it is known that MHE results from mutations in the EXT1 and EXT2 genes, which are crucial for producing heparan sulfate (HS), the precise cellular origins and molecular mechanisms of MHE are not fully understood. In our study, we discovered that in Ext1 mutant mice, osteochondromas arise from progenitor cells similar to mesenchymal stem cells located in the perichondrium. We identified that increased BMP signaling in these progenitor cells is the main defect leading to osteochondroma development. We observed that these perichondrial progenitor cells, including those in the groove of Ranvier, express high levels of HS. Targeted deletion of Ext1 in the perichondrium resulted in osteochondroma formation. Additionally, Ext1-deficient perichondrial progenitor cells exhibited heightened BMP signaling and more chondrogenic differentiation both in vitro and in vivo. Consistent with the role of enhanced BMP signaling in osteochondromagenesis, treatment with the BMP inhibitor LDN-193189 reduced osteochondroma formation in two MHE mouse models. Our findings highlight the importance of increased perichondrial BMP signaling in osteochondromagenesis and suggest that BMP inhibitors LDN-193189 could be a potential therapeutic option for MHE.