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A model of inflammatory arthritis highlights a role for oncostatin M in pro-inflammatory cytokine-induced bone destruction via RANK/RANKL.

Hui W, Cawston TE, Richards CD, Rowan AD - Arthritis Res. Ther. (2004)

Bottom Line: However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown.Furthermore, there was increased expression of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control.The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Musculoskeletal Research Group, The Medical School, University of Newcastle, Newcastle upon Tyne, UK. wang.hui@ncl.ac.uk

ABSTRACT
Oncostatin M is a pro-inflammatory cytokine previously shown to promote marked cartilage destruction both in vitro and in vivo when in combination with IL-1 or tumour necrosis factor alpha. However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown. Using adenoviral gene transfer, we have overexpressed oncostatin M in combination with either IL-1 or tumour necrosis factor alpha intra-articularly in the knees of C57BL/6 mice. Both of these combinations induced marked bone damage and markedly increased tartrate-resistant acid phosphatase-positive multinucleate cell staining in the synovium and at the front of bone erosions. Furthermore, there was increased expression of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control. This model of inflammatory arthritis demonstrates that, in vivo, oncostatin M in combination with either IL-1 or tumour necrosis factor alpha represents cytokine combinations that promote bone destruction. The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction.

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Intra-articular overexpression of oncostatin M (OSM) with either IL-1 or tumour necrosis factor alpha (TNF-α) increases RANK/RANKL expression in murine joints. Mice were injected intra-articularly with adenoviral vectors as described in Fig. 1, and the animals were sacrificed at day 7 following administration. Sections (n = 4 per treatment group) were immunolocalized with antibodies specific for (a)–(f) RANK or (g)–(l) RANKL with haematoxylin counterstaining. No positive staining (brown) was observed in the controls (a and g), while similar patterns of RANK and RANKL staining were observed in the synovium and inflammatory cells in joints treated with a single cytokine (representative data are shown: (b) TNF-α, (h) IL-1). This expression was further enhanced by the combinations of OSM + IL-1 (c, e, i, k) or OSM + TNF-α (d, f, j, l), especially at sites of bone erosion (arrows). A marked increase in RANK and RANKL expression was also seen in the articular chondrocytes for both cytokine combinations (e, f, k, l). b, bone; bm, bone marrow; c, cartilage; i, inflammatory cells; s, synovial cells. Bar = 50 μm.
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Figure 4: Intra-articular overexpression of oncostatin M (OSM) with either IL-1 or tumour necrosis factor alpha (TNF-α) increases RANK/RANKL expression in murine joints. Mice were injected intra-articularly with adenoviral vectors as described in Fig. 1, and the animals were sacrificed at day 7 following administration. Sections (n = 4 per treatment group) were immunolocalized with antibodies specific for (a)–(f) RANK or (g)–(l) RANKL with haematoxylin counterstaining. No positive staining (brown) was observed in the controls (a and g), while similar patterns of RANK and RANKL staining were observed in the synovium and inflammatory cells in joints treated with a single cytokine (representative data are shown: (b) TNF-α, (h) IL-1). This expression was further enhanced by the combinations of OSM + IL-1 (c, e, i, k) or OSM + TNF-α (d, f, j, l), especially at sites of bone erosion (arrows). A marked increase in RANK and RANKL expression was also seen in the articular chondrocytes for both cytokine combinations (e, f, k, l). b, bone; bm, bone marrow; c, cartilage; i, inflammatory cells; s, synovial cells. Bar = 50 μm.

Mentions: There was little or no RANK-positive staining in synovial tissues taken from control joints (Fig. 4a). Increased RANK expression associated with inflammatory and synovial cells was observed following treatment with TNF-α (Fig. 4b), and similar levels of expression were observed for OSM and IL-1 (data not shown). RANK expression was increased further, especially at the bone erosion fronts, when OSM was combined with IL-1 or TNF-α (Fig. 4c,4d). Interestingly, RANK appeared to be expressed as a gradient from the synovial tissue where increased numbers of RANK-positive cells were observed close to the cortical bone and periosteum of the patella, the femur and the tibia. Diffuse RANK staining in the superficial layer of cartilage was seen for the joints treated with each of the vectors separately (see Fig. 4b; some data not shown), and this staining was more intense in the joints treated with OSM + IL-1 or with OSM + TNF-α (Fig. 4e,4f).


A model of inflammatory arthritis highlights a role for oncostatin M in pro-inflammatory cytokine-induced bone destruction via RANK/RANKL.

Hui W, Cawston TE, Richards CD, Rowan AD - Arthritis Res. Ther. (2004)

Intra-articular overexpression of oncostatin M (OSM) with either IL-1 or tumour necrosis factor alpha (TNF-α) increases RANK/RANKL expression in murine joints. Mice were injected intra-articularly with adenoviral vectors as described in Fig. 1, and the animals were sacrificed at day 7 following administration. Sections (n = 4 per treatment group) were immunolocalized with antibodies specific for (a)–(f) RANK or (g)–(l) RANKL with haematoxylin counterstaining. No positive staining (brown) was observed in the controls (a and g), while similar patterns of RANK and RANKL staining were observed in the synovium and inflammatory cells in joints treated with a single cytokine (representative data are shown: (b) TNF-α, (h) IL-1). This expression was further enhanced by the combinations of OSM + IL-1 (c, e, i, k) or OSM + TNF-α (d, f, j, l), especially at sites of bone erosion (arrows). A marked increase in RANK and RANKL expression was also seen in the articular chondrocytes for both cytokine combinations (e, f, k, l). b, bone; bm, bone marrow; c, cartilage; i, inflammatory cells; s, synovial cells. Bar = 50 μm.
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Related In: Results  -  Collection

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Figure 4: Intra-articular overexpression of oncostatin M (OSM) with either IL-1 or tumour necrosis factor alpha (TNF-α) increases RANK/RANKL expression in murine joints. Mice were injected intra-articularly with adenoviral vectors as described in Fig. 1, and the animals were sacrificed at day 7 following administration. Sections (n = 4 per treatment group) were immunolocalized with antibodies specific for (a)–(f) RANK or (g)–(l) RANKL with haematoxylin counterstaining. No positive staining (brown) was observed in the controls (a and g), while similar patterns of RANK and RANKL staining were observed in the synovium and inflammatory cells in joints treated with a single cytokine (representative data are shown: (b) TNF-α, (h) IL-1). This expression was further enhanced by the combinations of OSM + IL-1 (c, e, i, k) or OSM + TNF-α (d, f, j, l), especially at sites of bone erosion (arrows). A marked increase in RANK and RANKL expression was also seen in the articular chondrocytes for both cytokine combinations (e, f, k, l). b, bone; bm, bone marrow; c, cartilage; i, inflammatory cells; s, synovial cells. Bar = 50 μm.
Mentions: There was little or no RANK-positive staining in synovial tissues taken from control joints (Fig. 4a). Increased RANK expression associated with inflammatory and synovial cells was observed following treatment with TNF-α (Fig. 4b), and similar levels of expression were observed for OSM and IL-1 (data not shown). RANK expression was increased further, especially at the bone erosion fronts, when OSM was combined with IL-1 or TNF-α (Fig. 4c,4d). Interestingly, RANK appeared to be expressed as a gradient from the synovial tissue where increased numbers of RANK-positive cells were observed close to the cortical bone and periosteum of the patella, the femur and the tibia. Diffuse RANK staining in the superficial layer of cartilage was seen for the joints treated with each of the vectors separately (see Fig. 4b; some data not shown), and this staining was more intense in the joints treated with OSM + IL-1 or with OSM + TNF-α (Fig. 4e,4f).

Bottom Line: However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown.Furthermore, there was increased expression of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control.The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Musculoskeletal Research Group, The Medical School, University of Newcastle, Newcastle upon Tyne, UK. wang.hui@ncl.ac.uk

ABSTRACT
Oncostatin M is a pro-inflammatory cytokine previously shown to promote marked cartilage destruction both in vitro and in vivo when in combination with IL-1 or tumour necrosis factor alpha. However, the in vivo effects of these potent cytokine combinations on bone catabolism are unknown. Using adenoviral gene transfer, we have overexpressed oncostatin M in combination with either IL-1 or tumour necrosis factor alpha intra-articularly in the knees of C57BL/6 mice. Both of these combinations induced marked bone damage and markedly increased tartrate-resistant acid phosphatase-positive multinucleate cell staining in the synovium and at the front of bone erosions. Furthermore, there was increased expression of RANK and its ligand RANKL in the inflammatory cells, in inflamed synovium and in articular cartilage of knee joints treated with the cytokine combinations compared with expression in joints treated with the cytokines alone or the control. This model of inflammatory arthritis demonstrates that, in vivo, oncostatin M in combination with either IL-1 or tumour necrosis factor alpha represents cytokine combinations that promote bone destruction. The model also provides further evidence that increased osteoclast-like, tartrate-resistant acid phosphatase-positive staining multinucleate cells and upregulation of RANK/RANKL in joint tissues are key factors in pathological bone destruction.

Show MeSH
Related in: MedlinePlus