| First Author | Mundy C | Year | 2026 |
| Journal | Bone | Volume | 209 |
| Pages | 117913 | PubMed ID | 42070715 |
| Mgi Jnum | J:385368 | Mgi Id | MGI:8331371 |
| Doi | 10.1016/j.bone.2026.117913 | Citation | Mundy C, et al. (2026) Progenitors from distinct perichondrium layers initiate tumor formation in hereditary multiple osteochondromas as revealed in a mouse model. Bone 209:117913 |
| abstractText | 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 Pdgfralpha-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 Pdgfralpha-CreER;Ext1(f/f) and Fgf18-CreER;Ext1(f/f) mice were injected with tamoxifen and monitored for tumor development over time. By 4-8 weeks post-tamoxifen, osteochondromas had formed in Pdgfralpha;Ext1 mutants targeting both layers, but none were appreciable in Fgf18;Ext1 mutants targeting the outer layer, based on muCT scans, histochemistry and td-Tomato cell lineage tracing. In situ analyses verified that Ext1 had been ablated in the outer layer of Fgf18;Ext1 mutants. Analyses also showed that the developing osteochondromas in the Pdgfralpha;Ext1 mutants displayed strong expression of cartilage proteins and abundant pSMAD1 and pSMAD2 proteins that mediate pro-chondrogenic BMP/TGFbeta signals. The data provide new evidence that perichondrium progenitors, and more specifically inner layer cells delineated by Pdgfralpha expression, initiate osteochondroma formation, being redirected into an ectopic chondrogenic program by Ext1 loss and deficiency of its vital function. |
