Hereditary multiple exostoses: are there new plausible treatment strategies?

Abstract

Introduction: Hereditary multiple exostoses (HME) is a rare congenital pediatric disorder characterized by osteochondromas forming next to the growth plates in young patients. The osteochondromas cause multiple health problems that include skeletal deformities and chronic pain. Surgery is used to remove the most symptomatic osteochondromas but because of their large number, many are left in place, causing life-long problems and increasing the probability of malignant transformation. There is no other treatment to prevent or reduce osteochondromas formation at present.

Areas covered: Recent studies reviewable through PubMed are providing new insights into cellular and molecular mechanisms of osteochondroma development. The resulting data are suggesting rational and plausible new therapeutic strategies for osteochondroma prevention some of which are being tested in HME animal models and one of which is part of a just announced clinical trial.

Expert commentary: This section summarizes and evaluates such strategies and points also to possible future alternatives.

Keywords: Drug treatment; EXT1; EXT2; Heparan Sulfate; Hereditary Multiple Exostoses; Multiple Osteochondroma; Multiple Osteochondromas; Signaling proteins; Signaling proteins and pathways.

Figure 1

Schematic illustrates multiple phenotypic changes that occur during the development of osteochondromas. (A) Formation of osteochondromas (OC, yellow) invariably occurs along the border between growth plate (cells in blue) and perichondrium (PC). The osteochondroma cells exhibit a germline heterozygous EXT1 or EXT2 mutation in addition to a “second hit” and thus are genetically different from neighboring growth plate or perichondrial cells. It is also well established that osteochondroma tissue masses contain a variable number of neighboring cells (in blue) recruited into the tumor-formation process and are thus heterogeneous in terms of cell composition. (B) The mutant phenotype of cells along the growth plate-perichondrium border is complex and involves multiple regulatory reciprocal changes that converge into promoting osteochondroma development. The decreases in EXT expression and HS levels (in combination with a second hit) would decrease the activities of such anti-chondrogenic mechanisms as FGF/ERK/MEK signaling and Noggin and Gremlin expression [76]. Concurrently, there would be reciprocal increases in pro-chondrogenic mechanisms including BMP and hedgehog signaling and heparanase expression. It is possible of course that there could be other changes providing further support to osteochondroma growth (illustrated by the question mark).