Role of CDMP-1 in Skeletal Morphogenesis: Promotion of Mesenchymal Cell Recruitment and Chondrocyte Differentiation

Abstract

Cartilage provides the template for endochondral ossification and is crucial for determining the length and width of the skeleton. Transgenic mice with targeted expression of recombinant cartilage-derived morphogenetic protein-1 (CDMP-1), a member of the bone morphogenetic protein family, were created to investigate the role of CDMP-1 in skeletal formation. The mice exhibited chondrodysplasia with expanded cartilage, which consists of the enlarged hypertrophic zone and the reduced proliferating chondrocyte zone. Histologically, CDMP-1 increased the number of chondroprogenitor cells and accelerated chondrocyte differentiation to hypertrophy. Expression of CDMP-1 in the notochord inhibited vertebral body formation by blocking migration of sclerotome cells to the notochord. These results indicate that CDMP-1 antagonizes the ventralization signals from the notochord. Our study suggests a molecular mechanism by which CDMP-1 regulates the formation, growth, and differentiation of the skeletal elements.

Kinetics of tamoxifen‐regulated Cre activity in mice using a cartilage‐specific CreERT to assay temporal activity windows along the proximodistal limb skeleton

“…1A; Tsumaki et al, 1999). Twelve transgenic founders were evaluated in crosses to the Rosa26 LacZ reporter line to generate embryos for analysis of Cre recombinase activity by assessing the LacZ reporter activation.…”

“…1A) for insertion of coding sequences to be expressed, such as LacZ (pKN185 from Y. Yamada; Tsumaki et al, 1999). The CreER T coding region (Feil et al, 1996) was isolated as an EcoRI fragment and blunt-end ligated into the NotI cloning site.…”

“…A small enhancer region located within the first intron of the Col2a1 gene, in conjunction with ϳ1kb of the Col2a1 promoter region (see Fig. 1A), efficiently drives transgenic reporter expression and recapitulates the tissue-specific patterns of Col2a1 gene expression in vivo Zhou et al, 1995;Krebsbach et al, 1996;Tsumaki et al, 1999;Ovchinnikov et al, 2000). A conditionally active Cre recombinase under the control of the Col2a1 promoter would enable the use of this robust promoter to drive expression transiently in the chondrogenic lineage without the unwanted side effects of expression in other critical signaling structures in the early embryo (e.g., notochord, AER).…”

Mechanisms of digit formation: Human malformation syndromes tell the story

“…2). Overexpression of Gdf5 in chicken or mouse limbs enlarges the initial condensations and increases cartilage nodules in limb explant cultures (Francis-West et al, 1996;Francis-West et al, 1999a;Tsumaki et al, 1999) pointing toward a positive role in chondrogenesis. Due to its restricted expression pattern in developing joint, Gdf5 has early on been ascribed a role in joint development (Storm and Kingsley, 1996), based on the observation that mice with mutations in Gdf5 (brachypodism, bp; Storm et al, 1994; see also Fig.…”

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

“…Indeed, there appear to be several negative feedback loops (directly or indirectly) involved in regulating the pathway at specific points, such as FGFs at the level of the proliferating chondrocyte (Naski et al, 1998), PTHrP at the level of the prehypertrophic chondrocyte Lanske et al, 1996;Weir et al, 1996) and Ihh at the level of hypertrophic cells Kameda et al, 1999;Pathi et al, 1999;. Positive regulators include Cdmp1, Bmp2 and Bmp6, which have been shown to influence growth and maturation of chondrocytes (Enomoto-Iwamoto et al, 1998;Gimsrud et al, 1999;Kawakami et al, 1996;Tsumaki et al, 1999), while Bmp4 and Bmp7 appear to act negatively (Katagiri et al, 1998a;Marazzi et al, 1997). As for earlier developmental processes, the actions of BMPs can be antagonized by Noggin (Brunet et al, 1998).…”