The plausibility of a theory for pathogenesis of an osteochondroma depends on its adherence to all available data regarding the implicated pathways involved and its ability to explain the character of the resulting lesion. Both Ihh diffusion and FGF-R3 signal transduction are demonstrably dependent on HSPGs present at the cell surface. Loss of EXT function results in HSPG synthesis deficiency. The proliferative results of lost FGF-R3 signaling and the focal absence of the bone collar from disrupted Ihh diffusion to the perichondrium have each been shown independently, as discussed above. While other signaling pathways are undoubtedly affected by loss of HSPGs in a clone of chondrocytes, the predictable effects on these two pathways form a theory for osteochondroma pathogenesis which fits all the available evidence.
In addition, this pathogenetic theory explains some of the characteristics of an osteochondroma. First, means for the creation of the resultant structural morphology of an osteochondroma are provided by the theory. The radiographic diagnosis of an osteochondroma depends upon demonstration of cortical and medullary continuity. In this theory, the osteochondroma cap forms from chondrocytes proliferating in the peripheral direction, but from the otherwise normal proliferative zone of the physis (see Figure 5D
). Therefore the fronts of chondrocyte differentiation, hypertrophy, and apoptosis, and subsequent primary spongiosal ossification are in continuity with those in the rest of the physis. In addition, the focal distruption of the bone collar, which is then restored epiphyseally once the next wildtype clone of cells moves through the proliferative zone, provides a mechanism for the diagnostically important cortical continuity.
A final feature of the osteochondroma which any pathogenetic theory must address, is that of malignant degeneration into a surface chondrosarcoma. This was once thought to happen in up to 25 percent of patients with HME37
. While that figure has more recently been reduced to 0.5 to 3%21,55,69,72
, the resulting surface chondrosarcomas do make up approximately one sixth of all the chondrosarcomas in humans 60
. While this theory for osteochondroma pathogenesis does not entirely explain malignant degeneration, it explains a scenario which is predisposed toward accumulation of genetic mutations; this would, at a certain frequency, lead to malignant degeneration.
In a classic parallel, familial adenomatous polyposis leads to colorectal cancer because a given population of cells accumulates somatic mutations while undergoing more than the usual number of cell cycles prior to terminal differentiation67
. This theory of osteochondroma pathogenesis includes an extension of chondrocyte generations from a single clone due to disrupted FGF-R3 signaling. This necessarily increases risk for accumulating important malignant somatic mutations by genomic replication error alone. However, in contrast to the case of familial adenomatous polyposis, the osteochondroma cells are not intrinsically immortalized by the EXT mutations in this theory. Instead, they are freed from a potent extracellular restraint to cell cycling. Once the extracellular restraint of FGF-R3 signaling is removed, extended cell cycle iteration is permitted and with it, the increased stochastic likelihood of other proneoplastic mutations. Thus, the putative tumor suppressor function of EXT genes is not only indirect, but only enables oncogenesis in a specific milieu of extracellular signals.