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The nuclear factor of activated T cells (NFAT) transcription factor NFATp (NFATc2) is a repressor of chondrogenesis.

Ranger AM, Gerstenfeld LC, Wang J, Kon T, Bae H, Gravallese EM, Glimcher MJ, Glimcher LH - J. Exp. Med. (2000)

Bottom Line: Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway.Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype.Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

ABSTRACT
Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.

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Cartilage cell proliferation in articular cartilage and in extraarticular connective tissue in NFATp−/− mice. (A and B) Low power (original magnification: ×20) of the femoral heads and acetabula of 12-mo-old control +/− (A) and NFATp−/− mutant (B) mice, showing thickening of articular cartilage and sites of extraarticular cartilage cell proliferation and joint destruction in the mutant animal. (C) High power (original magnification: ×200) of B, showing invasion of the acetabulum by proliferating cartilage cells (black arrows) and obliteration of the joint space (white arrows) with loss of safranin-O staining (*). (D) Femoral head and extraarticular connective tissues of 3-mo-old NFATp−/− mouse (original magnification: ×100), clearly demonstrating the physical separation of the sites of articular and extraarticular cartilage proliferation. (E) Extraarticular connective tissues of 3-mo-old NFATp−/− mouse demonstrating the differentiation of resident cells into ordered columnar cartilage (arrows). (F) High power (original magnification: ×200) of E. (G) Extraarticular connective tissues of 6-mo-old NFATp−/− mouse showing calcification of cartilage and the beginnings of endochondral ossification in the extraarticular soft tissue (original magnification: ×200). ac, articular cartilage; fh, femoral head; a, acetabulum; ea, extraarticular; ob, osteoblasts; oc, osteocytes; cc, calcified cartilage; b, bone.
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Figure 2: Cartilage cell proliferation in articular cartilage and in extraarticular connective tissue in NFATp−/− mice. (A and B) Low power (original magnification: ×20) of the femoral heads and acetabula of 12-mo-old control +/− (A) and NFATp−/− mutant (B) mice, showing thickening of articular cartilage and sites of extraarticular cartilage cell proliferation and joint destruction in the mutant animal. (C) High power (original magnification: ×200) of B, showing invasion of the acetabulum by proliferating cartilage cells (black arrows) and obliteration of the joint space (white arrows) with loss of safranin-O staining (*). (D) Femoral head and extraarticular connective tissues of 3-mo-old NFATp−/− mouse (original magnification: ×100), clearly demonstrating the physical separation of the sites of articular and extraarticular cartilage proliferation. (E) Extraarticular connective tissues of 3-mo-old NFATp−/− mouse demonstrating the differentiation of resident cells into ordered columnar cartilage (arrows). (F) High power (original magnification: ×200) of E. (G) Extraarticular connective tissues of 6-mo-old NFATp−/− mouse showing calcification of cartilage and the beginnings of endochondral ossification in the extraarticular soft tissue (original magnification: ×200). ac, articular cartilage; fh, femoral head; a, acetabulum; ea, extraarticular; ob, osteoblasts; oc, osteocytes; cc, calcified cartilage; b, bone.

Mentions: In NFATp−/− mice, visual inspection of the hip joint revealed abnormalities of the articular cartilage and also revealed extraarticular masses of cartilage that not only were spatially distinct from one another in the extraarticular soft tissues but also were easily separable manually from the joint. The articular cartilage in NFATp−/− mice was grayish in color compared with wt littermates and had a visibly roughened surface in contrast to the smooth, polished appearance of the wt control articular cartilage. Both gross analysis and a careful longitudinal histologic analysis were performed on many animals, ranging in age from 2.5–20 mo, and representative sections are shown in Fig. 2. Light microscopic analysis demonstrated proliferation of abnormal-looking cartilage cells in the articular cartilage ( Fig. 2A and Fig. B), most apparent in older female animals. When this proliferation occurred, it was apparent in the layer of already existing cartilage cells above the zone of calcified cartilage ( Fig. 2A–C). In the most severe cases, as in the 1-yr-old animal shown, there was extensive degradation of the cartilage and destruction of the joint ( Fig. 2B and Fig. C).


The nuclear factor of activated T cells (NFAT) transcription factor NFATp (NFATc2) is a repressor of chondrogenesis.

Ranger AM, Gerstenfeld LC, Wang J, Kon T, Bae H, Gravallese EM, Glimcher MJ, Glimcher LH - J. Exp. Med. (2000)

Cartilage cell proliferation in articular cartilage and in extraarticular connective tissue in NFATp−/− mice. (A and B) Low power (original magnification: ×20) of the femoral heads and acetabula of 12-mo-old control +/− (A) and NFATp−/− mutant (B) mice, showing thickening of articular cartilage and sites of extraarticular cartilage cell proliferation and joint destruction in the mutant animal. (C) High power (original magnification: ×200) of B, showing invasion of the acetabulum by proliferating cartilage cells (black arrows) and obliteration of the joint space (white arrows) with loss of safranin-O staining (*). (D) Femoral head and extraarticular connective tissues of 3-mo-old NFATp−/− mouse (original magnification: ×100), clearly demonstrating the physical separation of the sites of articular and extraarticular cartilage proliferation. (E) Extraarticular connective tissues of 3-mo-old NFATp−/− mouse demonstrating the differentiation of resident cells into ordered columnar cartilage (arrows). (F) High power (original magnification: ×200) of E. (G) Extraarticular connective tissues of 6-mo-old NFATp−/− mouse showing calcification of cartilage and the beginnings of endochondral ossification in the extraarticular soft tissue (original magnification: ×200). ac, articular cartilage; fh, femoral head; a, acetabulum; ea, extraarticular; ob, osteoblasts; oc, osteocytes; cc, calcified cartilage; b, bone.
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Related In: Results  -  Collection

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Figure 2: Cartilage cell proliferation in articular cartilage and in extraarticular connective tissue in NFATp−/− mice. (A and B) Low power (original magnification: ×20) of the femoral heads and acetabula of 12-mo-old control +/− (A) and NFATp−/− mutant (B) mice, showing thickening of articular cartilage and sites of extraarticular cartilage cell proliferation and joint destruction in the mutant animal. (C) High power (original magnification: ×200) of B, showing invasion of the acetabulum by proliferating cartilage cells (black arrows) and obliteration of the joint space (white arrows) with loss of safranin-O staining (*). (D) Femoral head and extraarticular connective tissues of 3-mo-old NFATp−/− mouse (original magnification: ×100), clearly demonstrating the physical separation of the sites of articular and extraarticular cartilage proliferation. (E) Extraarticular connective tissues of 3-mo-old NFATp−/− mouse demonstrating the differentiation of resident cells into ordered columnar cartilage (arrows). (F) High power (original magnification: ×200) of E. (G) Extraarticular connective tissues of 6-mo-old NFATp−/− mouse showing calcification of cartilage and the beginnings of endochondral ossification in the extraarticular soft tissue (original magnification: ×200). ac, articular cartilage; fh, femoral head; a, acetabulum; ea, extraarticular; ob, osteoblasts; oc, osteocytes; cc, calcified cartilage; b, bone.
Mentions: In NFATp−/− mice, visual inspection of the hip joint revealed abnormalities of the articular cartilage and also revealed extraarticular masses of cartilage that not only were spatially distinct from one another in the extraarticular soft tissues but also were easily separable manually from the joint. The articular cartilage in NFATp−/− mice was grayish in color compared with wt littermates and had a visibly roughened surface in contrast to the smooth, polished appearance of the wt control articular cartilage. Both gross analysis and a careful longitudinal histologic analysis were performed on many animals, ranging in age from 2.5–20 mo, and representative sections are shown in Fig. 2. Light microscopic analysis demonstrated proliferation of abnormal-looking cartilage cells in the articular cartilage ( Fig. 2A and Fig. B), most apparent in older female animals. When this proliferation occurred, it was apparent in the layer of already existing cartilage cells above the zone of calcified cartilage ( Fig. 2A–C). In the most severe cases, as in the 1-yr-old animal shown, there was extensive degradation of the cartilage and destruction of the joint ( Fig. 2B and Fig. C).

Bottom Line: Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway.Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype.Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

ABSTRACT
Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.

Show MeSH
Related in: MedlinePlus