Homozygous achondroplasia: Morphologic and biochemical study of cartilage

Abstract

We have performed histochemical, immunohistochemical, electron microscopic, and biochemical studies on the upper tibial cartilage from a case of homozygous achondroplasia. The growth zone was narrow and disorganized. Columnization was absent except for a few areas with short rows of cells. Hypertrophy was reduced to scattered clusters of cells. The provisional calcification was patchy and primary trabeculae were thick and irregularly arranged. Islands of fibrous or fibrocartilagineous tissue were found along the growth zone. The matrix did not stain with safranin O and lacked metachromasia, except for pericellular rims around the hypertrophic cell clusters. Staining with antibodies against the large proteoglycan monomers and chondroitin-4-sulfate was weakly positive. Electron microscopic examination showed that only a few cells had degenerative signs. In most areas of the matrix, proteoglycan granules were absent. Areas with dense collagen fibers were seen. In contrast to the growth zone, the cartilage of the remaining epiphyses had normal histochemical, immunohistochemical, and electron microscopic appearance. The large proteoglycan monomers had a normal composition and hydrodynamic size. Type II and XI collagen, pepsin fragments of type IX collagen, and several noncollagenous proteins extracted from cartilage had a normal electrophoretic migration. It is suggested that a mutation affecting a matrix component or a regulatory pathway present only or predominantly in the growth area of the chondroepiphysis might explain the findings.

FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway

“…However, FGF-treated STAT-1 −/− metatarsals exhibited some increase in length and width compared to controls, which could be due to the unmasking of the growth stimulatory effects of FGF signaling when the STAT-1-mediated growth inhibitory pathway is blocked. Thus, treatment with FGF of E15 bone rudiments appears to mimic the inhibition of endochondral ossification and bone development observed in human fetuses with homozygous ACH or TD and in mouse models (Shah et al 1973;Stanescu et al 1990;Li et al 1999). We show that this effect also requires STAT-1 function.…”

Activation of FGF receptors by mutations in the transmembrane domain

“…It is quite possible that similar activating mutations could occur in other residues in the transmembrane region, but that their e ect could be too strong to be compatible with survival. It is worth noting that although ACH is dominant, the homozygous mutation is generally lethal at or shortly after birth (Stanescu et al, 1990) and that FGFR-3, although predominantly expressed in the cartilage of long bones, is also expressed in other organs. It is quite possible that while subtle activating e ects are compatible with survival, stronger e ects would not be, and thus often be undetected.…”

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…HCH is characterized by mild short stature and shares some clinical features with ACH (Bellus et al 1995). TD is characterized by a very severe skeletal dysplasia and is clinically similar to homozygous cases of ACH (Stanescu et al 1990). Both TD and homozygous ACH are generally lethal during the first several months of life.…”