Mutations in ROR2 result in a spectrum of genetic disorders in humans that are classified, depending on the nature of the mutation and the clinical phenotype, as either autosomal dominant brachydactyly type B (BDB, MIM 113000) or recessive Robinow syndrome (RRS, MIM 268310). In an attempt to model BDB in mice, the mutation W749X was engineered into the mouse Ror2 gene. In contrast to the human situation, mice heterozygous for Ror2 W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2 W749FLAG/W749FLAG and a previously engineered mutant, Ror2 TMlacZ/TMlacZ , lack the P2/P3 joint. Absence of Gdf5 expression at the corresponding interzone suggests that the defect is in specification of the joint. As this phenotype is absent in mice lacking the entire Ror2 gene, it appears that specification of the P2/P3 joint is affected by ROR2 activity. Finally, Ror2 W749FLAG/W749FLAG mice survive to adulthood and exhibit phenotypes (altered body composition, reduced male fertility) not observed in Ror2 knockout mice, presumably due to the perinatal lethality of the latter. Therefore, Ror2 W749FLAG/W749FLAG mice represent a postnatal model for RRS, provide insight into the mechanism of joint specification, and uncover novel roles of Ror2 in the mouse.
Bone morphogenetic proteins (BMPs) are secreted by skeletal cells, induce the differentiation of mesenchymal cells into cells of the osteoblastic lineage, and increase their differentiated function. BMPs also decrease collagenase-3 expression by the osteoblast. We tested the autocrine role of BMPs on collagenase-3 expression in osteoblast-enriched cells from fetal rat calvariae (Ob cells) by examining the effects of noggin, a specific inhibitor of BMP binding and function. Although collagenase-3 transcript expression declined in untreated Ob cells in culture over a 24-h period, BMP-2, -4, and -6 decreased collagenase-3 messenger RNA levels in cells treated for 2-24 h. The addition of noggin prevented the decrease of collagenase-3 transcripts in control cultures, opposed the inhibitory actions of BMP-2, and increased the levels of the protease in the culture medium. Noggin did not alter the decay of collagenase-3 messenger RNA in transcriptionally arrested cells, and it increased the levels of collagenase-3 heterogeneous nuclear RNA in Ob cells. In conclusion, noggin enhances the synthesis of collagenase-3 in osteoblasts, supporting the notion that BMPs act as autocrine suppressors of collagenase-3 in skeletal cells, an effect that may contribute to the maintenance of the bone matrix.
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