PPAR-γ agonist rosiglitazone prevents inflammatory periodontal bone loss by inhibiting osteoclastogenesis

Hassumi, Márcio Yukio; Silva-Filho, Vilmar J.; Campos-Júnior, Jozafá C.; Vieira, Sílvio M.; Cunha, Fernando; Alves, Polyanna Miranda; Alves, José Bento; Kawai, Toshihisa; Gonçalves, Reginaldo Bruno; Napimoga, Marcelo Henrique

doi:10.1016/j.intimp.2009.06.002

Cited by 51 publications

(53 citation statements)

References 32 publications

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“…The identification of RANKL, its receptor RANK, and the soluble decoy receptor OPG has contributed significantly to the understanding of the skeletal remodeling mechanism involved in the osteoclastogenesis process (29). Considerable efforts are being made to identify drugs able to inhibit RANKL or increase OPG, to adjust the RANKL/OPG ratio in several diseases (30)(31)(32), as well as to develop the use of human OPG constructs, which can powerfully inhibit bone resorption (33,34). More recently, a fully human mAb that binds and inhibits RANKL, called denosumab (AMG 162), was suggested as a promising drug able to reduce biochemical markers of bone resorption (35) in patients with multiple myeloma or bone metastases (36).…”

Section: Discussionmentioning

confidence: 99%

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

Napimoga

Silva

Carregaro

et al. 2012

The Journal of Immunology

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The 15-deoxy-Δ12,14-PG J2 (15d-PGJ2) has demonstrated excellent anti-inflammatory results in different experimental models. It can be used with a polymeric nanostructure system for modified drug release, which can change the therapeutic properties of the active principle, leading to increased stability and slower/prolonged release. The aim of the current study was to test a nanotechnological formulation as a carrier for 15d-PGJ2, and to investigate the immunomodulatory effects of this formulation in a mouse periodontitis model. Poly (D,L-lactide-coglycolide) nanocapsules (NC) were used to encapsulate 15d-PGJ2. BALB/c mice were infected on days 0, 2, and 4 with Aggregatibacter actinomycetemcomitans and divided into groups (n = 5) that were treated daily during 15 d with 1, 3, or 10 μg/kg 15d-PGJ2-NC. The animals were sacrificed, the submandibular lymph nodes were removed for FACS analysis, and the jaws were analyzed for bone resorption by morphometry. Immunoinflammatory markers in the gingival tissue were analyzed by reverse transcriptase-quantitative PCR, Western blotting, or ELISA. Infected animals treated with the 15d-PGJ2-NC presented lower bone resorption than infected animals without treatment (p < 0.05). Furthermore, infected animals treated with 10 μg/kg 15d-PGJ2-NC had a reduction of CD4+CD25+FOXP3+ cells and CD4/CD8 ratio in the submandibular lymph node (p < 0.05). Moreover, CD55 was upregulated, whereas RANKL was downregulated in the gingival tissue of the 10 μg/kg treated group (p < 0.05). Several proinflammatory cytokines were decreased in the group treated with 10 μg/kg 15d-PGJ2-NC, and high amounts of 15d-PGJ2 were observed in the gingiva. In conclusion, the 15d-PGJ2-NC formulation presented immunomodulatory effects, decreasing bone resorption and inflammatory responses in a periodontitis mouse model.

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Section: Discussionmentioning

confidence: 99%

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

Napimoga

Silva

Carregaro

et al. 2012

The Journal of Immunology

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“…The latter finding is consistent with previous studies that showed downregulation of RANKL by PPARg agonist in murine bone marrow stromal cells in vitro. (57,58) In female mice, there was no discernible skeletal phenotype in PPARg mice during the whole growing phase (1 to 32 weeks) of life. Notably, bone loss was accelerated only after ovariectomy in PPARg female mice compared with wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Cho

Yang

Her

et al. 2011

Journal of Bone and Mineral Research

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PPARg has critical role in the differentiation of mesenchymal stem cells into adipocytes while suppressing osteoblastic differentiation. We generated transgenic mice that overexpress PPARg specifically in osteoblasts under the control of a 2.3-kb procollagen type 1 promoter (Col.1-PPARg). Bone mineral density (BMD) of 6-to 14-week-old Col.1 À PPARg male mice was 8% to 10% lower than that of their wildtype littermates, whereas no difference was noticed in Col.1-PPARg female mice. Col.1-PPARg male mice exhibited decreased bone volume (45%), trabecular thickness (23%), and trabecular number (27%), with a reciprocal increase in trabecular spacing (51%). Dynamic histomorphometric analysis also revealed that bone-formation rate (42%) and mineral apposition rate (32%) were suppressed significantly in Col.1-PPARg male mice compared with their wild-type littermates. Interestingly, osteoclast number and surface also were decreased by 40% and 58%, respectively, in Col.1-PPARg male mice. In vitro whole-marrow culture for osteoclastogenesis also showed a significant decrease in osteoclast formation (approximately 35%) with the cells from Col.1-PPARg male mice, and OPG/RANKL ratio was reduced in stromal cells from Col.1-PPARg male mice. Although there was no significant difference in BMD in Col.1-PPARg female mice up to 30 weeks, bone loss was accelerated after ovariectomy compared with wild-type female mice (À3.9% versus À6.8% at 12 weeks after ovariectomy, p < .01), indicating that the effects of PPARg overexpression becomes more evident in an estrogen-deprived state in female mice. In conclusion, in vivo osteoblast-specific overexpression of PPARg negatively regulates bone mass in male mice and accelerates estrogen-deficiency-related bone loss in female mice. ß

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“…As a consequence of the important roles, PPARs play in controlling metabolic homeostasis and inflammatory processes, they are often the therapeutic molecular targets for metabolic diseases such as diabetes (Chinetti et al 2000) and in the treatment of inflammatory disorders (Napimoga et al 2008, Hassumi et al 2009, Klotz et al 2009, Park et al 2009). In the present paper, we have investigated the effects of the 15d-PGJ 2 , an agonist of PPAR-γ, on disease outcome and immune function in T. cruzi-infected C57BL/6 mice.…”

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confidence: 99%

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

Rodrigues

Miguel

Chica

et al. 2010

Mem. Inst. Oswaldo Cruz

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The acute phase of Trypanosoma cruzi infection is associated with a strong inflammatory reaction in the heart characterised by a massive infiltration of immune cells that is dependent on the T. cruzi strain and the host response. 15d-PGJ2 belongs to a new class of anti-inflammatory compounds with possible clinical applications. We evaluated the effects of 15d-PGJ2 administered during the acute phase of T. cruzi infection in mice. Mice were infected with the Colombian strain of T. cruzi and subsequently treated with 15d-PGJ2 repeatedly for seven days. The inflammatory infiltrate was examined by histologic analysis. Slides were immunohistochemically stained to count the number and the relative size of parasite nests. Infection-induced changes in serum cytokine levels were measured by ELISA. The results demonstrated that treatment with 15d-PGJ2 reduced the inflammatory infiltrate in the skeletal muscle at the site of infection and decreased the number of lymphocytes and neutrophils in the blood. In addition, we found that 15d-PGJ2 led to a decrease in the relative volume density of amastigote nests in cardiac muscle. T. cruzi-infected animals treated with 15d-PGJ2 displayed a statistically significant increase in IL-10 levels with no change in IFN-γ levels. Taken together, we demonstrate that treatment with 15d-PGJ2 in the acute phase of Chagas disease led to a controlled immune response with decreased numbers of amastigote nests, as measured by the volume density

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PPAR-γ agonist rosiglitazone prevents inflammatory periodontal bone loss by inhibiting osteoclastogenesis

Cited by 51 publications

References 32 publications

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

Exogenous Administration of 15d-PGJ2–Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

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