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Evidence for the prevention of enthesitis in HLA-B27/hβ(2)m transgenic rats treated with a monoclonal antibody against TNF-α.

Milia AF, Ibba-Manneschi L, Manetti M, Benelli G, Generini S, Messerini L, Matucci-Cerinic M - J. Cell. Mol. Med. (2011)

Bottom Line: Early TNF-α blockade prevented, and late treatment improved IBD signs in B27TR.Anti-TNF-α treatment reduced inflammation and preserved the enthesis organization in most animals.Early TNF-α blockade prevents the onset of IBD and consequently the development of enthesitis in peripheral joints in the B27TR model of human SpA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy. milia_af@yahoo.it

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Representative immunohistochemical results of phosphorylated Smad1/5/8 in the peripheral joints of HLA-B27 transgenic rats (B27TR). (A), (B) 18-week-old IgG2a,k treated B27TR. (B) is a higher magnification view of boxed area in (A). Smad1/5/8 signalling is detected in spindle-shaped entheseal fibroblast-like cells (black arrowhead), inflammatory cells (white arrowhead), and in round chondroblast-like cells (black arrows) at entheseal level. (C), (D) 27-week-old IgG2a,k treated B27TR. (D) is a higher magnification view of boxed area in (C). Proliferating (white arrowhead) and prehypertrophic (black arrow) chondrocyte-like cells show phosphorylated Smad1/5/8-immunopositivity in the fibrocartilage at the point of entheseal attachment. Hypertrophic chondrocytes are negative (black arrowhead). (E), (F) 27-week-old IgG2a,k treated B27TR. (F) is a higher magnification view of boxed area in (E). Immunopositive proliferating chondrocytes are evident in the articular cartilage (black arrow). (G), (H) 18-week-old anti-TNF-α treated B27TR. Absence of phosphorylated Smad1/5/8 immunopositivity in the articular cartilage (G) and at the entheseal level (H). (I), (J) 27-week-old anti-TNF-α treated B27TR. (J) is a higher magnification view of boxed area in (I). Proliferating chondrocytes in the fibrocartilaginous point of entheseal attachment show strong immunopositivity for phosphorylated Smad1/5/8 (black arrow). Original magnification: (G) ×10; (A, C, E, H, I) ×20; (B, D, F, J): ×40.
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fig05: Representative immunohistochemical results of phosphorylated Smad1/5/8 in the peripheral joints of HLA-B27 transgenic rats (B27TR). (A), (B) 18-week-old IgG2a,k treated B27TR. (B) is a higher magnification view of boxed area in (A). Smad1/5/8 signalling is detected in spindle-shaped entheseal fibroblast-like cells (black arrowhead), inflammatory cells (white arrowhead), and in round chondroblast-like cells (black arrows) at entheseal level. (C), (D) 27-week-old IgG2a,k treated B27TR. (D) is a higher magnification view of boxed area in (C). Proliferating (white arrowhead) and prehypertrophic (black arrow) chondrocyte-like cells show phosphorylated Smad1/5/8-immunopositivity in the fibrocartilage at the point of entheseal attachment. Hypertrophic chondrocytes are negative (black arrowhead). (E), (F) 27-week-old IgG2a,k treated B27TR. (F) is a higher magnification view of boxed area in (E). Immunopositive proliferating chondrocytes are evident in the articular cartilage (black arrow). (G), (H) 18-week-old anti-TNF-α treated B27TR. Absence of phosphorylated Smad1/5/8 immunopositivity in the articular cartilage (G) and at the entheseal level (H). (I), (J) 27-week-old anti-TNF-α treated B27TR. (J) is a higher magnification view of boxed area in (I). Proliferating chondrocytes in the fibrocartilaginous point of entheseal attachment show strong immunopositivity for phosphorylated Smad1/5/8 (black arrow). Original magnification: (G) ×10; (A, C, E, H, I) ×20; (B, D, F, J): ×40.

Mentions: Immunohistochemistry was performed to identify cells expressing TNF-α in the affected joints of IgG2a,k-treated B27TR. In both 18- and 27-week-old rats, chondrocyte-like cells showed immunopositivity for TNF-α in the proliferating zone of the articular cartilage and at the fibrocartilaginous point of attachment of the entheses (Fig. 4A–C). Some vessels close to the entheses showed positive cells for TNF-α. In addition, immunostaining for nuclear phosphorylated Smad 1/5/8 (p-Smad1/5/8), a marker for active bone morphogenetic protein (BMP) signalling [17], was performed. Activation of Smad1/5/8 signalling was detected in spindle-shaped entheseal fibroblast-like cells, inflammatory cells and in round chondroblast-like cells (Fig. 5A, B). Moreover, proliferating and prehypertrophic chondrocyte-like cells showed strong p-Smad1/5/8-immunopositivity in the fibrocartilage at the point of entheseal attachment (Fig. 5C, D). Instead, hypertrophic chondrocytes were negative (Fig. 5D). Chondrocytes in the articular cartilage were also found positive for p-Smad1/5/8 (Fig. 5E, F). No difference in p-Smad1/5/8 expression was found between 18- and 27-week-old IgG2a,k-treated B27TR.


Evidence for the prevention of enthesitis in HLA-B27/hβ(2)m transgenic rats treated with a monoclonal antibody against TNF-α.

Milia AF, Ibba-Manneschi L, Manetti M, Benelli G, Generini S, Messerini L, Matucci-Cerinic M - J. Cell. Mol. Med. (2011)

Representative immunohistochemical results of phosphorylated Smad1/5/8 in the peripheral joints of HLA-B27 transgenic rats (B27TR). (A), (B) 18-week-old IgG2a,k treated B27TR. (B) is a higher magnification view of boxed area in (A). Smad1/5/8 signalling is detected in spindle-shaped entheseal fibroblast-like cells (black arrowhead), inflammatory cells (white arrowhead), and in round chondroblast-like cells (black arrows) at entheseal level. (C), (D) 27-week-old IgG2a,k treated B27TR. (D) is a higher magnification view of boxed area in (C). Proliferating (white arrowhead) and prehypertrophic (black arrow) chondrocyte-like cells show phosphorylated Smad1/5/8-immunopositivity in the fibrocartilage at the point of entheseal attachment. Hypertrophic chondrocytes are negative (black arrowhead). (E), (F) 27-week-old IgG2a,k treated B27TR. (F) is a higher magnification view of boxed area in (E). Immunopositive proliferating chondrocytes are evident in the articular cartilage (black arrow). (G), (H) 18-week-old anti-TNF-α treated B27TR. Absence of phosphorylated Smad1/5/8 immunopositivity in the articular cartilage (G) and at the entheseal level (H). (I), (J) 27-week-old anti-TNF-α treated B27TR. (J) is a higher magnification view of boxed area in (I). Proliferating chondrocytes in the fibrocartilaginous point of entheseal attachment show strong immunopositivity for phosphorylated Smad1/5/8 (black arrow). Original magnification: (G) ×10; (A, C, E, H, I) ×20; (B, D, F, J): ×40.
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fig05: Representative immunohistochemical results of phosphorylated Smad1/5/8 in the peripheral joints of HLA-B27 transgenic rats (B27TR). (A), (B) 18-week-old IgG2a,k treated B27TR. (B) is a higher magnification view of boxed area in (A). Smad1/5/8 signalling is detected in spindle-shaped entheseal fibroblast-like cells (black arrowhead), inflammatory cells (white arrowhead), and in round chondroblast-like cells (black arrows) at entheseal level. (C), (D) 27-week-old IgG2a,k treated B27TR. (D) is a higher magnification view of boxed area in (C). Proliferating (white arrowhead) and prehypertrophic (black arrow) chondrocyte-like cells show phosphorylated Smad1/5/8-immunopositivity in the fibrocartilage at the point of entheseal attachment. Hypertrophic chondrocytes are negative (black arrowhead). (E), (F) 27-week-old IgG2a,k treated B27TR. (F) is a higher magnification view of boxed area in (E). Immunopositive proliferating chondrocytes are evident in the articular cartilage (black arrow). (G), (H) 18-week-old anti-TNF-α treated B27TR. Absence of phosphorylated Smad1/5/8 immunopositivity in the articular cartilage (G) and at the entheseal level (H). (I), (J) 27-week-old anti-TNF-α treated B27TR. (J) is a higher magnification view of boxed area in (I). Proliferating chondrocytes in the fibrocartilaginous point of entheseal attachment show strong immunopositivity for phosphorylated Smad1/5/8 (black arrow). Original magnification: (G) ×10; (A, C, E, H, I) ×20; (B, D, F, J): ×40.
Mentions: Immunohistochemistry was performed to identify cells expressing TNF-α in the affected joints of IgG2a,k-treated B27TR. In both 18- and 27-week-old rats, chondrocyte-like cells showed immunopositivity for TNF-α in the proliferating zone of the articular cartilage and at the fibrocartilaginous point of attachment of the entheses (Fig. 4A–C). Some vessels close to the entheses showed positive cells for TNF-α. In addition, immunostaining for nuclear phosphorylated Smad 1/5/8 (p-Smad1/5/8), a marker for active bone morphogenetic protein (BMP) signalling [17], was performed. Activation of Smad1/5/8 signalling was detected in spindle-shaped entheseal fibroblast-like cells, inflammatory cells and in round chondroblast-like cells (Fig. 5A, B). Moreover, proliferating and prehypertrophic chondrocyte-like cells showed strong p-Smad1/5/8-immunopositivity in the fibrocartilage at the point of entheseal attachment (Fig. 5C, D). Instead, hypertrophic chondrocytes were negative (Fig. 5D). Chondrocytes in the articular cartilage were also found positive for p-Smad1/5/8 (Fig. 5E, F). No difference in p-Smad1/5/8 expression was found between 18- and 27-week-old IgG2a,k-treated B27TR.

Bottom Line: Early TNF-α blockade prevented, and late treatment improved IBD signs in B27TR.Anti-TNF-α treatment reduced inflammation and preserved the enthesis organization in most animals.Early TNF-α blockade prevents the onset of IBD and consequently the development of enthesitis in peripheral joints in the B27TR model of human SpA.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy. milia_af@yahoo.it

Show MeSH
Related in: MedlinePlus