Progenitors from distinct perichondrium layers initiate tumor formation in hereditary multiple osteochondromas as revealed in a mouse model.

Hereditary Multiple Osteochondromas (HMO) is a rare, pediatric disease characterized by osteochondromas that form next to the growth plates, accumulate over time and cause major health problems. Most HMO cases are linked to loss-of-function mutations in Golgi-resident proteins EXT1 or EXT2, but tumor development remains unclear. In particular, the source of tumor-forming progenitors has long been debated, with recent studies pointing to a perichondrial origin. Perichondrium normally flanks the growth plates, has essential roles in skeletal growth, and is composed of an inner cuboidal cell layer and an outer fibroblastic cell layer. Here, we set out to determine by genetic approaches whether the tumors do in fact derive from perichondrium and if one or both layers provide progenitors. We employed Pdgfrα-CreER and Fgf18-CreER transgenic mice that respectively, target inner and outer layers or the outer layer only. Mice were mated with floxed Ext1 mice to conditionally ablate the causative gene, mimicking tumor induction in patients. Compound juvenile Pdgfrα-CreER;Ext1