BMP action in skeletogenesis involves attenuation of retinoid signaling

Abstract

The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.

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).…”

Expression of key retinoic acid modulating genes suggests active regulation during development and regeneration of the amphibian limb

“…Both Crabp2 and Raldh2 are also expressed interdigitally in mouse autopods (Niederreither et al, 1997;Ruberte et al, 1992), and syndactyly (fusion of the digits, extra phalanges) occurs in Crabp2 knockout mice (Lampron et al, 1995) suggesting that the normal function of RA at this stage is to keep developing digits separated. Raldh2 expression, and therefore RA synthesis, is restricted to interdigital regions in mice by the direct action of prochondrogenic BMPs, which attenuate Raldh2 expression (Hoffman et al, 2006).…”

Genetic deletion ofCyp26b1negatively impacts limb skeletogenesis by inhibiting chondrogenesis

“…The activity of this reporter has been shown to tightly correlate with chondroblast differentiation and cartilage formation (Hoffman et al, 2006;Muramatsu et al, 2007;Weston et al, 2000). Col2-LUC reporter activity in Cyp26b1 -/-PLM cultures was around seven-times lower than that in the wild type after only 1 day of culture (Fig.…”