Retinoic acid treatment induces type X collagen gene expression in cultured chick chondrocytes

Pacifici, Maurizio; Golden, Eleanor B.; Iwamoto, Masahiro; Adams, Sherrill L.

doi:10.1016/0014-4827(91)90497-i

Cited by 97 publications

(67 citation statements)

References 46 publications

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“…Similar observations were previously reported with primary chick chondrocytes (32,33). As for chick chondrocytes, we observed that a significant response to RA occurred at physiological doses of the vitamin, but very high concentrations were necessary to obtain maximal stimulation.…”

Section: Discussionsupporting

confidence: 90%

Type X collagen gene expression in mouse chondrocytes immortalized by a temperature-sensitive simian virus 40 large tumor antigen.

Lefebvre

Garofalo

Crombrugghe

1995

The Journal of Cell Biology

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Abstract. Mouse endochondral chondrocytes were immortalized with a temperature-sensitive simian virus 40 large tumor antigen. Several clonal isolates as well as pools of immortalized cells were characterized. In monolayer cultures at the temperature permissive for the activity of the large tumor antigen (32°C), the cells grew continuously with a doubling time of ,~2 d, whereas they stopped growing at nonpermissive temperatures (37°C-39°C). The cells from all pools and from most clones expressed the genes for several markers of hypertrophic chondrocytes, such as type X collagen, matrix Gla protein, and osteopontin, but had lost expression of type lI collagen mRNA and failed to be stained by alcian blue which detects cartilagespecific proteoglycans. The cells also contained mRNAs for type I collagen and bone Gla protein, consistent with acquisition of osteoblastic-like properties. Higher levels of mRNAs for type X collagen, bone Gla protein, and osteopontin were found at nonpermissive temperatures, suggesting that the expression of these genes was upregulated upon growth arrest, as is the case in vivo during chondrocyte hypertrophy. Cells also retained their ability to respond to retinoic acid, as indicated by retinoic acid dose-dependent and timedependent increases in type X collagen mRNA levels. These cell lines, the first to express characteristic features of hypertrophic chondrocytes, should be very useful to study the regulation of the type X collagen gene and other genes activated during the last stages of chondrocyte differentiation. C HONDROCYTES are highly specialized cells that are derived from mesenchymal cells during embryonic development to form the various cartilages of vertebrates. Chondrocytes are characterized by the production of cartHage-specific extracellular macromolecules including the collagen types H, IX, and XI, and the proteoglycan aggrecan (16). In permanent cartilages, the phenotype of chondrocytes is stably maintained, whereas in endochondral cartilages, chondrocytes undergo a further differentiation process (16,34). During this process, chondrocytes mature into hypertrophic ceils around which the cartilage matrix becomes calcified, and subsequently undergo apoptosis, making way for invading osteoblasts. Hypertrophic chondrocytes still contain type II collagen and aggrecan RNAs, although at reduced levels (21, 38), they are characterized by the synthesis of type X collagen, which is uniquely expressed by these cells (10,21,39), and by the expression of markers typically associated with osteoblasts. Both hypertrophic chondrocytes and osteoblasts have the ability to induce mineralization of the extracellular matrix and to produce alka-

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Section: Discussionsupporting

confidence: 90%

Type X collagen gene expression in mouse chondrocytes immortalized by a temperature-sensitive simian virus 40 large tumor antigen.

Lefebvre

Garofalo

Crombrugghe

1995

The Journal of Cell Biology

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“…In the early phases of chondrocyte differentiation, as it has been reported by several authors (17,23,28,33,35,44,47), retinoic acid either inhibits or induces chondrogenesis . At later stages of chondrocyte differentiation, retinoic acid stimulates chondrogenesis and promotes maturation of chondrocytes to stage II (hypertrophic, type X producing) (26)(27)(28)(29) and osteoblast-like cells (type I producing, mineralizing) (this report) . It is therefore evident that differentiating chondrocytes exhibit different responses to exogenous retinoic acid depending upon their differentiation stage.…”

Section: Discussionmentioning

confidence: 87%

Hypertrophic chondrocytes undergo further differentiation in culture

Cancedda

Gentili

Manduca

et al. 1992

The Journal of Cell Biology

190

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Abstract. Conditions have been defined for promoting growth and differentiation of hypertrophic chondrocytes obtained in culture starting from chick embryo tibiae . Hypertrophic chondrocytes, grown in suspension culture as described (Castagnola P., G. Moro, F. Descalzi Cancedda, and R. Cancedda . 1986. J. Cell Biol. 102 :2310-2317, when they reached the stage of single cells, were transferred to substrate-dependent culture conditions in the presence of ascorbic acid. Cells showed a change in morphology, became more elongated and flattened, expressed alkaline phosphatase, and eventually mineralized . Type II and X collagen synthesis was halted and replaced by type I collagen synthesis . In addition the cells started to produce and to secrete in large amount a protein with an apparent molecular mass of 82 KD in reducing conditions and 63 KD in unreducing conditions. This protein is soluble in acidic solutions, does not contain oNG bone organogenesis occurs in the embryo by endochondral ossification from undifferentiated mesenchyme. During the early stages of development, mesenchymal cells in the limb buds condense to form a core of differentiated chondrocytes ; osteogenesis starts at the periphery ofthe cartilage core, which is subsequently invaded by blood vessels and replaced by bone marrow and trabecular bone. After birth, similar events take place in the long bone growth plate and at the bone fracture sites. Bone formation and remodeling have been extensively investigated, starting from pioneering work describing the morphological and biochemical changes occurring during early bone formation to more recent studies aimed at the elucidations of the cellular and molecular mechanisms involved (7,22,34) . It is widely agreed that cells present in a continuous collar surrounding, but separated from the cartilage rudiment, give rise to osteoblasts, i.e., cells responsible for the synthesis and mineralization of the osteoid extracellular matrix . In the past, occasionally and recently more frequently, it has been postulated thatgrowth platehypertrophic chondrocytes might also contribute to the formation of a bone matrix, since in some organ culturesthese cells start to express bone markers . During culture of mouse mandibular condyles, the expression of type I collagen, osteonectin, alkaline phosphatase, osteopontin, and osteocalcin by mature chondrocytes was detected by in situ hybridization (38). A morphological study © The Rockefeller University Press, 0021-9525/92/04/427/9 $2 .00 The Journal of Cell Biology, Volume 117, Number 2, April 1992 427-435 collagenous domains, and is glycosylated . The Ch21 protein, a marker of hypertrophic chondrocytes and bone cells, was synthesized throughout the culture . We have defined this additional differentiation stage as an osteoblast-like stage . Calcium deposition in the extracellular matrix occurred regardless of the addition of ß glycerophosphate to the culture medium . Comparable results were obtained both when the cells were plated at low density and when they were alrea...

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“…Hypertrophy-We determined that ATRA-induced type X collagen expression, the cardinal marker for chondrocyte hypertrophy (40), was markedly reduced in primary TG2 (Ϫ/Ϫ) mouse chondrocytes (Fig. 5A).…”

Section: Tg2-dependent and -Independent Chondrocytementioning

confidence: 99%

Distinct Transglutaminase 2-independent and Transglutaminase 2-dependent Pathways Mediate Articular Chondrocyte Hypertrophy

Johnson

Etten

Nanda

et al. 2003

Journal of Biological Chemistry

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Altered chondrocyte differentiation, including development of chondrocyte hypertrophy, mediates osteoarthritis and pathologic articular cartilage matrix calcification. Similar changes in endochondral chondrocyte differentiation are essential for physiologic growth plate mineralization. In both articular and growth plate cartilages, chondrocyte hypertrophy is associated with up-regulated expression of certain protein-crosslinking enzymes (transglutaminases (TGs)) including the unique dualfunctioning TG and GTPase TG2. Here, we tested if TG2 directly mediates the development of chondrocyte hypertrophic differentiation. To do so, we employed normal bovine chondrocytes and mouse knee chondrocytes from recently described TG2 knockout mice, which are phenotypically normal. We treated chondrocytes with the osteoarthritis mediator IL-1␤, with the all-trans form of retinoic acid (ATRA), which promotes endochondral chondrocyte hypertrophy and pathologic calcification, and with C-type natriuretic peptide, an essential factor in endochondral development. IL-1␤ and ATRA induced TG transamidation activity and calcification in wild-type but not in TG2 (؊/؊) mouse knee chondrocytes. In addition, ATRA induced multiple features of hypertrophic differentiation (including type X collagen, alkaline phosphatase, and MMP-13), and these effects required TG2. Significantly, TG2 (؊/؊) chondrocytes lost the capacity for ATRA-induced expression of Cbfa1, a transcription factor necessary for ATRA-induced chondrocyte hypertrophy. Finally, C-type natriuretic peptide, which did not modulate TG activity, comparably promoted Cbfa1 expression and hypertrophy (without associated calcification) in TG2 (؉/؉) and TG2 (؊/؊) chondrocytes. Thus, distinct TG2-independent and TG2-dependent mechanisms promote Cbfa1 expression, articular chondrocyte hypertrophy, and calcification. TG2 is a potential site for intervention in pathologic calcification promoted by IL-1␤ and ATRA.In physiologic endochondral growth plate mineralization, chondrocytes undergo a multi-step differentiation process in which there is ordered progression from a resting to proliferative state followed by maturation to a terminally differentiated hypertrophic state (1). Hypertrophic chondrocytes are specialized to remodel and mineralize their matrix (2). For example, hypertrophic chondrocytes demonstrate up-regulated expression of MMP-13, a mediator of matrix degradation in osteoarthritis (OA) 1 (3). In addition, hypertrophic chondrocytes demonstrate altered patterns of collagen subtype generation that include stereotypic up-regulated type X collagen expression, and hypertrophic chondrocytes show markedly increased release of mineralization-competent secretory vesicles (2). In addition, hypertrophic chondrocytes demonstrate increased alkaline phosphatase (AP) activity and other alterations in the metabolism of P i and PP i (4, 6). In this context, P i and PP i mediate both calcification and growth plate organization (5), and P i promotes chondrocyte hypertrophy (6).In contrast to chondroc...

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Retinoic acid treatment induces type X collagen gene expression in cultured chick chondrocytes

Cited by 97 publications

References 46 publications

Type X collagen gene expression in mouse chondrocytes immortalized by a temperature-sensitive simian virus 40 large tumor antigen.

Type X collagen gene expression in mouse chondrocytes immortalized by a temperature-sensitive simian virus 40 large tumor antigen.

Hypertrophic chondrocytes undergo further differentiation in culture

Distinct Transglutaminase 2-independent and Transglutaminase 2-dependent Pathways Mediate Articular Chondrocyte Hypertrophy

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