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Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways.

Weston AD, Rosen V, Chandraratna RA, Underhill TM - J. Cell Biol. (2000)

Bottom Line: Underhill. 1997.These findings show that BMP and RAR-signaling pathways appear to operate independently to coordinate skeletal development, and that retinoid signaling can function in a BMP-independent manner to induce cartilage formation.Thus, retinoid signaling appears to play a novel and unexpected role in skeletogenesis by regulating the emergence of chondroblasts from skeletal progenitors.

View Article: PubMed Central - PubMed

Affiliation: Division of Oral Biology, School of Dentistry, The University of Western Ontario, London, Ontario, Canada.

ABSTRACT
The generation of the paraxial skeleton requires that commitment and differentiation of skeletal progenitors is precisely coordinated during limb outgrowth. Several signaling molecules have been identified that are important in specifying the pattern of these skeletal primordia. Very little is known, however, about the mechanisms regulating the differentiation of limb mesenchyme into chondrocytes. Overexpression of RARalpha in transgenic animals interferes with chondrogenesis and leads to appendicular skeletal defects (Cash, D.E., C.B. Bock, K. Schughart, E. Linney, and T.M. Underhill. 1997. J. Cell Biol. 136:445-457). Further analysis of these animals shows that expression of the transgene in chondroprogenitors maintains a prechondrogenic phenotype and prevents chondroblast differentiation even in the presence of BMPs, which are known stimulators of cartilage formation. Moreover, an RAR antagonist accelerates chondroblast differentiation as demonstrated by the emergence of collagen type II-expressing cells much earlier than in control or BMP-treated cultures. Addition of Noggin to limb mesenchyme cultures inhibits cartilage formation and the appearance of precartilaginous condensations. In contrast, abrogation of retinoid signaling is sufficient to induce the expression of the chondroblastic phenotype in the presence of Noggin. These findings show that BMP and RAR-signaling pathways appear to operate independently to coordinate skeletal development, and that retinoid signaling can function in a BMP-independent manner to induce cartilage formation. Thus, retinoid signaling appears to play a novel and unexpected role in skeletogenesis by regulating the emergence of chondroblasts from skeletal progenitors.

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Model for the role of the BMP- and RA-signaling pathways in limb skeletal development. Mesenchymal cells become committed to a chondrogenic cell fate by signals that are not well defined. Stabilization and expansion of this committed cell population appears to require the action of the BMPs. The availability of BMPs along with RA is important for the maintenance of prechondrogenic cell populations present in precartilaginous condensations and the perichondrium. Loss of RAR activity induces skeletal progenitor differentiation and emergence of the chondroblast phenotype. In the absence of BMP signals, chondroprogenitors that continue RARα expression loose their prechondrogenic phenotype. Genes within boxes represent their expression in those cell types in vivo.
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Figure 7: Model for the role of the BMP- and RA-signaling pathways in limb skeletal development. Mesenchymal cells become committed to a chondrogenic cell fate by signals that are not well defined. Stabilization and expansion of this committed cell population appears to require the action of the BMPs. The availability of BMPs along with RA is important for the maintenance of prechondrogenic cell populations present in precartilaginous condensations and the perichondrium. Loss of RAR activity induces skeletal progenitor differentiation and emergence of the chondroblast phenotype. In the absence of BMP signals, chondroprogenitors that continue RARα expression loose their prechondrogenic phenotype. Genes within boxes represent their expression in those cell types in vivo.

Mentions: A proposed model for the action of BMP and RAR signaling in early limb skeletogenesis, those stages involved with establishment of chondrogenic elements, is illustrated in Fig. 7. During limb outgrowth chondroprogenitors do not spontaneously differentiate into chondroblasts. Instead, their differentiation is temporally regulated during limb bud outgrowth, such that proximal cells within the limb bud differentiate before distal cells. Similarly, appositional growth of the cartilages is mediated by the spatiotemporal differentiation of perichondrial cells to chondrocytes (Bairati et al. 1996). RAR activity in conjunction with a BMP signal in prechondrogenic condensations and the perichondrium in vivo are required for the expression of the prechondrogenic phenotype. The maintenance of a population of prechondrogenic cells such as those in the perichondrium may therefore be attributed to the continued activity of these gene products in this region (von Schroeder and Heersche 1998; Koyama et al. 1999). Loss of RAR activity in limb precartilaginous condensations or perichondrial cells leads to their differentiation, contributing to longitudinal and appositional cartilage growth, respectively.


Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways.

Weston AD, Rosen V, Chandraratna RA, Underhill TM - J. Cell Biol. (2000)

Model for the role of the BMP- and RA-signaling pathways in limb skeletal development. Mesenchymal cells become committed to a chondrogenic cell fate by signals that are not well defined. Stabilization and expansion of this committed cell population appears to require the action of the BMPs. The availability of BMPs along with RA is important for the maintenance of prechondrogenic cell populations present in precartilaginous condensations and the perichondrium. Loss of RAR activity induces skeletal progenitor differentiation and emergence of the chondroblast phenotype. In the absence of BMP signals, chondroprogenitors that continue RARα expression loose their prechondrogenic phenotype. Genes within boxes represent their expression in those cell types in vivo.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169377&req=5

Figure 7: Model for the role of the BMP- and RA-signaling pathways in limb skeletal development. Mesenchymal cells become committed to a chondrogenic cell fate by signals that are not well defined. Stabilization and expansion of this committed cell population appears to require the action of the BMPs. The availability of BMPs along with RA is important for the maintenance of prechondrogenic cell populations present in precartilaginous condensations and the perichondrium. Loss of RAR activity induces skeletal progenitor differentiation and emergence of the chondroblast phenotype. In the absence of BMP signals, chondroprogenitors that continue RARα expression loose their prechondrogenic phenotype. Genes within boxes represent their expression in those cell types in vivo.
Mentions: A proposed model for the action of BMP and RAR signaling in early limb skeletogenesis, those stages involved with establishment of chondrogenic elements, is illustrated in Fig. 7. During limb outgrowth chondroprogenitors do not spontaneously differentiate into chondroblasts. Instead, their differentiation is temporally regulated during limb bud outgrowth, such that proximal cells within the limb bud differentiate before distal cells. Similarly, appositional growth of the cartilages is mediated by the spatiotemporal differentiation of perichondrial cells to chondrocytes (Bairati et al. 1996). RAR activity in conjunction with a BMP signal in prechondrogenic condensations and the perichondrium in vivo are required for the expression of the prechondrogenic phenotype. The maintenance of a population of prechondrogenic cells such as those in the perichondrium may therefore be attributed to the continued activity of these gene products in this region (von Schroeder and Heersche 1998; Koyama et al. 1999). Loss of RAR activity in limb precartilaginous condensations or perichondrial cells leads to their differentiation, contributing to longitudinal and appositional cartilage growth, respectively.

Bottom Line: Underhill. 1997.These findings show that BMP and RAR-signaling pathways appear to operate independently to coordinate skeletal development, and that retinoid signaling can function in a BMP-independent manner to induce cartilage formation.Thus, retinoid signaling appears to play a novel and unexpected role in skeletogenesis by regulating the emergence of chondroblasts from skeletal progenitors.

View Article: PubMed Central - PubMed

Affiliation: Division of Oral Biology, School of Dentistry, The University of Western Ontario, London, Ontario, Canada.

ABSTRACT
The generation of the paraxial skeleton requires that commitment and differentiation of skeletal progenitors is precisely coordinated during limb outgrowth. Several signaling molecules have been identified that are important in specifying the pattern of these skeletal primordia. Very little is known, however, about the mechanisms regulating the differentiation of limb mesenchyme into chondrocytes. Overexpression of RARalpha in transgenic animals interferes with chondrogenesis and leads to appendicular skeletal defects (Cash, D.E., C.B. Bock, K. Schughart, E. Linney, and T.M. Underhill. 1997. J. Cell Biol. 136:445-457). Further analysis of these animals shows that expression of the transgene in chondroprogenitors maintains a prechondrogenic phenotype and prevents chondroblast differentiation even in the presence of BMPs, which are known stimulators of cartilage formation. Moreover, an RAR antagonist accelerates chondroblast differentiation as demonstrated by the emergence of collagen type II-expressing cells much earlier than in control or BMP-treated cultures. Addition of Noggin to limb mesenchyme cultures inhibits cartilage formation and the appearance of precartilaginous condensations. In contrast, abrogation of retinoid signaling is sufficient to induce the expression of the chondroblastic phenotype in the presence of Noggin. These findings show that BMP and RAR-signaling pathways appear to operate independently to coordinate skeletal development, and that retinoid signaling can function in a BMP-independent manner to induce cartilage formation. Thus, retinoid signaling appears to play a novel and unexpected role in skeletogenesis by regulating the emergence of chondroblasts from skeletal progenitors.

Show MeSH
Related in: MedlinePlus