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Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling.

Boileau C, Tat SK, Pelletier JP, Cheng S, Martel-Pelletier J - Arthritis Res. Ther. (2008)

Bottom Line: In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K.Moreover, these drugs effectively blocked the IL-1beta effect on the osteoclast differentiation process and the survival of mature osteoclasts.Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec, H2L 4M1, Canada.

ABSTRACT

Introduction: Subchondral bone alterations represent an essential component of osteoarthritis (OA). Modifying the abnormal subchondral bone metabolism may be indicated to treat OA. We investigated the effect of diacerein and rhein on the changes occurring in subchondral bone during OA. To this end, we determined the drugs' effects on metalloprotease-13 (MMP-13) synthesis on subchondral bone and on the osteoblast signalling pathways. In osteoclasts, we studied MMP-13 and cathepsin K production as well as cell differentiation, proliferation, and survival.

Methods: The effect of diacerein/rhein on the production of subchondral bone MMP-13 was determined by enzyme-linked immunosorbent assay. Signalling pathways were evaluated on osteoblasts by Western blot. Osteoclast experiments were performed using cells from the pre-osteoclastic murine cell line Raw 264.7. Osteoclast MMP-13 and cathepsin K activities were determined by specific bioassays and differentiation of these cells quantified by tartrate-resistant acid phosphatase staining.

Results: Diacerein and rhein reduced, in a dose-dependent manner, the interleukin-1-beta (IL-1beta)-induced MMP-13 production in OA subchondral bone. This effect occurred through the inhibition of ERK1/2 (extracellular signal-regulated kinase-1/2) and p38. In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K. Moreover, these drugs effectively blocked the IL-1beta effect on the osteoclast differentiation process and the survival of mature osteoclasts.

Conclusion: Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.

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Related in: MedlinePlus

Effect of diacerein and rhein on osteoclast (a) proliferation/differentiation and (b) total cells. Raw 264.7 cells were incubated for 7 days with RANKL (100 ng/mL) in the presence or absence of interleukin-1-beta (IL-1β) (100 pg/mL) and diacerein or rhein (20 μg/mL). The number of differentiated osteoclasts was determined by the tartrate-resistant acid phosphatase staining assay. Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control. RANKL, receptor activator of nuclear factor-κB ligand.
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Figure 6: Effect of diacerein and rhein on osteoclast (a) proliferation/differentiation and (b) total cells. Raw 264.7 cells were incubated for 7 days with RANKL (100 ng/mL) in the presence or absence of interleukin-1-beta (IL-1β) (100 pg/mL) and diacerein or rhein (20 μg/mL). The number of differentiated osteoclasts was determined by the tartrate-resistant acid phosphatase staining assay. Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control. RANKL, receptor activator of nuclear factor-κB ligand.

Mentions: Cells were treated from the first day (before formation of differentiated/mature osteoclasts) with RANKL in the absence or presence of IL-1β and diacerein or rhein at 20 μg/mL (n = 6). After the seventh day of incubation, cells were processed for TRAP staining and multinuclear cells as well as the total number of cells were quantified. As expected, there was a differentiation process of Raw 264.7 cells under RANKL treatment, which was associated with an increase in the rate of osteoclast formation under IL-1β stimulation. Interestingly, diacerein and rhein markedly and significantly inhibited osteoclast differentiation to a level that was even lower than the basal level. Moreover, the drugs also significantly decreased the proliferation rate of the Raw 264.7 cells (Figure 6b) as the total cell number, after 7 days of culture, was significantly lower under treatment with both diacerein and rhein.


Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling.

Boileau C, Tat SK, Pelletier JP, Cheng S, Martel-Pelletier J - Arthritis Res. Ther. (2008)

Effect of diacerein and rhein on osteoclast (a) proliferation/differentiation and (b) total cells. Raw 264.7 cells were incubated for 7 days with RANKL (100 ng/mL) in the presence or absence of interleukin-1-beta (IL-1β) (100 pg/mL) and diacerein or rhein (20 μg/mL). The number of differentiated osteoclasts was determined by the tartrate-resistant acid phosphatase staining assay. Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control. RANKL, receptor activator of nuclear factor-κB ligand.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483463&req=5

Figure 6: Effect of diacerein and rhein on osteoclast (a) proliferation/differentiation and (b) total cells. Raw 264.7 cells were incubated for 7 days with RANKL (100 ng/mL) in the presence or absence of interleukin-1-beta (IL-1β) (100 pg/mL) and diacerein or rhein (20 μg/mL). The number of differentiated osteoclasts was determined by the tartrate-resistant acid phosphatase staining assay. Data are expressed as fold changes compared with IL-1β-treated control, which was assigned a value of 1. Statistical analysis was performed versus IL-1β-treated control. RANKL, receptor activator of nuclear factor-κB ligand.
Mentions: Cells were treated from the first day (before formation of differentiated/mature osteoclasts) with RANKL in the absence or presence of IL-1β and diacerein or rhein at 20 μg/mL (n = 6). After the seventh day of incubation, cells were processed for TRAP staining and multinuclear cells as well as the total number of cells were quantified. As expected, there was a differentiation process of Raw 264.7 cells under RANKL treatment, which was associated with an increase in the rate of osteoclast formation under IL-1β stimulation. Interestingly, diacerein and rhein markedly and significantly inhibited osteoclast differentiation to a level that was even lower than the basal level. Moreover, the drugs also significantly decreased the proliferation rate of the Raw 264.7 cells (Figure 6b) as the total cell number, after 7 days of culture, was significantly lower under treatment with both diacerein and rhein.

Bottom Line: In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K.Moreover, these drugs effectively blocked the IL-1beta effect on the osteoclast differentiation process and the survival of mature osteoclasts.Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec, H2L 4M1, Canada.

ABSTRACT

Introduction: Subchondral bone alterations represent an essential component of osteoarthritis (OA). Modifying the abnormal subchondral bone metabolism may be indicated to treat OA. We investigated the effect of diacerein and rhein on the changes occurring in subchondral bone during OA. To this end, we determined the drugs' effects on metalloprotease-13 (MMP-13) synthesis on subchondral bone and on the osteoblast signalling pathways. In osteoclasts, we studied MMP-13 and cathepsin K production as well as cell differentiation, proliferation, and survival.

Methods: The effect of diacerein/rhein on the production of subchondral bone MMP-13 was determined by enzyme-linked immunosorbent assay. Signalling pathways were evaluated on osteoblasts by Western blot. Osteoclast experiments were performed using cells from the pre-osteoclastic murine cell line Raw 264.7. Osteoclast MMP-13 and cathepsin K activities were determined by specific bioassays and differentiation of these cells quantified by tartrate-resistant acid phosphatase staining.

Results: Diacerein and rhein reduced, in a dose-dependent manner, the interleukin-1-beta (IL-1beta)-induced MMP-13 production in OA subchondral bone. This effect occurred through the inhibition of ERK1/2 (extracellular signal-regulated kinase-1/2) and p38. In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K. Moreover, these drugs effectively blocked the IL-1beta effect on the osteoclast differentiation process and the survival of mature osteoclasts.

Conclusion: Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.

Show MeSH
Related in: MedlinePlus