Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis

Abstract

Bone morphogenetic protein 4 (BMP4) and growth/differentiation factor 5 (GDF5) are closely related protein family members and regulate early cartilage patterning and differentiation. In this study, we compared the functional outcome of their actions systematically at various stages of chondrogenesis in mouse embryonic limb bud mesenchyme grown in micromass cultures. Overall, both growth factors enhanced cartilage growth and differentiation in these cultures. Uniquely, BMP4 not only accelerated the formation and maturation of cartilaginous nodules, but also induced internodular mesenchymal cells to express cartilage differentiation markers. On the other hand, GDF5 increased the number of prechondrogenic mesenchymal cell condensation and cartilaginous nodules, without altering the overall pattern of differentiation. In addition, GDF5 caused a more sustained elevated expression level of Sox9 relative to that associated with BMP4. BMP4 accelerated chondrocyte maturation throughout the cultures and sustained an elevated level of Col10 expression, whereas GDF5 caused a transient increase in Col10 expression. Taken together, we conclude that BMP4 is instructive to chondrogenesis and induces mesenchymal cells toward the chondrogenic lineage. Furthermore, BMP4 accelerates the progression of cartilage differentiation to maturation. GDF5 enhances cartilage formation by promoting chondroprogenitor cell aggregation, and amplifying the responses of cartilage differentiation markers. These differences may serve to fine-tune the normal cartilage differentiation program, and can be exploited for the molecular manipulation in biomimetics.

The influence of sex on the chondrogenic potential of muscle‐derived stem cells: Implications for cartilage regeneration and repair

“…MDSCs have previously been shown to have chondrogenic potential (24,25), especially after BMP-4 transduction. BMP-4 has also been demonstrated to enhance potential for chondrogenesis in vitro and in vivo in cell types other than MDSCs (38)(39)(40). It has also been reported that the combined effect of TGF␤3 and BMP-4 or BMP-2 on chondrogenic pellet size is greater than that of each growth factor administered separately (41,42).…”

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

“…Significant association of polymorphism in GDF-5 with KOA could be related to role of variant T allele to influence transcription of the GDF5 gene with the susceptible allele showing reduced transcriptional activity (Miyamoto et al, 2007). The reduced activity of GDF5 may inhibit the process of early cartilage differentiation (Hatakeyama et al, 2004). Genetic variations in the GDF5 locus have been reported to be involved in the pathogenesis of rheumatoid arthritis and to influence human height, hip axis length and fracture risk in the elderly (Rouault et al, 2010;Vaes et al, 2009).…”

“…Growth and differentiation factor 5 (GDF-5), also known as cartilage derived morphogenetic protein of Transforming Growth Factor-b (TGF-b) superfamily, plays an important role in the development, maintenance and repair of bone and cartilage. It has been shown that reduced transcriptional activity leads to decrease in cartilage synthesis (Francis-West et al, 1999;Hatakeyama et al, 2004;Southam et al, 2007) and to compensate for the cartilage space, the bone beneath thickens and spreads out form knobbly outgrowths (osteophytes).…”

Accelerated hypertrophic chondrocyte kinetics in GDF‐7 deficient murine tibial growth plates

“…While a role for GDF-7/BMP-12 in chondrocyte biology and growth plate kinetics has, to our knowledge, not been reported in the literature, there is extensive evidence implicating the related molecule, GDF-5, in chondrocyte differentiation and maturation. [1][2][3][4][5][6][7] Most recently, 5-week-old female mice deficient in GDF-5 were shown to have the opposite phenotype in the proximal tibial growth plate relative to that seen in the present study with GDF-7 deficient mice of the same age and sex. 8 Compared to control growth plates, the physes from GDF-5 À/À animals had slower growth rates that were associated with a longer hypertrophic phase duration, whereas, in our current study, GDF-7 deficient growth plates had faster growth rates that were associated with a shorter hypertrophic phase duration.…”

“…[1][2][3][4][5][6][7] Five-week-old female mice deficient in one of these molecules, GDF-5, have additionally been shown to exhibit a significant reduction in proximal tibial growth rate due to a lengthened hypertrophic phase duration. 8 Most recently, Miyamoto and colleagues have demonstrated that Gdf5 appears to be a susceptibility gene for osteoarthritis, and that decreased Gdf5 expression may be associated with the development of this degenerative joint disease.…”