The BMPs regulate many aspects of endochondral bone formation including the commitment and differentiation of mesenchymal cells to the chondrocytic lineage. During limb bud outgrowth, Bmp2 and Bmp4 are expressed adjacent to condensing mesenchyme, in the perichondrium and in the interdigital regions. Null mutant embryos do not survive much beyond embryonic day (E) 10.5, and thus have not been informative in sorting out the function of BMP2 and 4 in these regions. Subsequent studies, however, in which dominant-negative or constitutively active BMP type II receptors were used in vitro and in vivo, indicate that BMP signalling is a requisite step in cartilage formation (Zou et al 1997). These results are complemented by experiments in which BMPs were overexpressed in the developing chick limb, in that BMPs were found to stimulate cartilage formation and modify skeletal patterning (Duprez et al 1996). Under certain conditions, BMPs have also been found to promote apoptosis within the interdigital region (IDR) (Zou & Niswander 1996). Moreover, loss- or gain-of-function studies with Noggin, a secreted inhibitor of BMP2 and 4 with lower affinity for BMP7, have shown that BMP2 and 4 are important in skeletal development and that regulation of BMP signalling is required for delineation of the various skeletal elements (Brunet et al 1998, Capdevila & Johnson 1998). Mice deficient in BMP6 or BMP7 also present with skeletal defects including polydactyly in the hind limbs of Brnp7~l~ animals (Luo et al 1995). Thus, BMPs, especially 2, 4 and 7 are important in early limb skeletal development, likely in the commitment and differentiation of mesenchymal cells to chondrocytes.
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