An ectopic Hedgehog signaling axis drives directional tumor outgrowth in a mouse model of hereditary multiple osteochondromas

Osteochondromas characterize the rare pediatric disorder hereditary multiple osteochondromas (HMO). The tumors originate from the growth plate perichondrium along skeletal elements, appear first as ectopic cartilage, and then grow unidirectionally, colliding with and damaging surrounding structures. HMO is caused by mutations that affect the heparan sulfate (HS) synthases EXT1 or EXT2, leading to HS deficiency and aberrant activity of HS-binding growth factors. We investigated the signaling pathways and mechanisms underlying tumor growth in HMO using mice with conditional Ext1 deficiency in the growth plate and perichondrium. Developing tumors displayed active Hedgehog (Hh) signaling within their cartilaginous moiety and the presence of parathyroid hormone–related protein (PTHrP) at their distal edge, generating an ectopic Hh-PTHrP axis orthogonal to the one directing normal bone lengthening at the adjacent growth plate. In Ext1 mutants, loss of the Hh signaling effector Smoothened (Smo) reduced tumor growth, whereas heterozygous loss of the Smo inhibitor Patched1 (Ptch1) increased tumor growth. Two HS-binding growth factors that promote normal cartilage growth in the growth plate, BMP2 and activin A, did not exert their normal prochondrogenic activity when Hh signaling was blocked, demonstrating that Hh signaling is essential for chondrogenesis. Together, our findings show that osteochondromas usurp a physiological signaling mechanism to guide and propel their directional outgrowth, enabling them to damage surrounding tissues, and suggest potential targets for therapeutic intervention.