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Constitutional flavonoids derived from Epimedium dose-dependently reduce incidence of steroid-associated osteonecrosis not via direct action by themselves on potential cellular targets.

Zhang G, Wang XL, Sheng H, Xie XH, He YX, Yao XS, Li ZR, Lee KM, He W, Leung KS, Qin L - PLoS ONE (2009)

Bottom Line: However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events.The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways.The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis.

View Article: PubMed Central - PubMed

Affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.

ABSTRACT
Intravascular-thrombosis and extravascular-lipid-deposit are the two key pathogenic events considered to interrupt intraosseous blood supply during development of steroid-associated osteonecrosis (ON). However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events. The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways. The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis. These findings encourage designing clinical trials to investigate potential of EF in prevention of steroid-associated ON.

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Related in: MedlinePlus

Key characteristics for histopathological identification and histopathological data analysis.ON lesion was found with trabecular bone containing considerable empty lacunae and lack of marrow cells (B) when compared to normal bone (A). In ON+ rabbits, thrombi were predominantly found in small marrow vessels with lack of angiographic particles (C), and marrow was predominantly occupied by a numerous fat cells (B, C). (D) Incidence of ON in each group: CON (13/14, 93%), L-EF (9/16, 56%), M-EF (2/16, 13%), H-EF (1/16, 6%). (E) There was no significant difference in ON Extent among all the groups. (F) Thrombotic Vessel Counts, and (G) Fat Cell Area Fraction presented similarities in changing patter over time, i.e. either attenuated in the L-EF group or prevented in both the M-EF and H-EF group when compared to that in the CON group. Note: Arrow pointed particle was angiographic substance during microCT-based angiography (data not shown). • CON group; ⧫ L-EF group; ▪ M-EF group; ▴ H-EF group; * P<0.05
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pone-0006419-g003: Key characteristics for histopathological identification and histopathological data analysis.ON lesion was found with trabecular bone containing considerable empty lacunae and lack of marrow cells (B) when compared to normal bone (A). In ON+ rabbits, thrombi were predominantly found in small marrow vessels with lack of angiographic particles (C), and marrow was predominantly occupied by a numerous fat cells (B, C). (D) Incidence of ON in each group: CON (13/14, 93%), L-EF (9/16, 56%), M-EF (2/16, 13%), H-EF (1/16, 6%). (E) There was no significant difference in ON Extent among all the groups. (F) Thrombotic Vessel Counts, and (G) Fat Cell Area Fraction presented similarities in changing patter over time, i.e. either attenuated in the L-EF group or prevented in both the M-EF and H-EF group when compared to that in the CON group. Note: Arrow pointed particle was angiographic substance during microCT-based angiography (data not shown). • CON group; ⧫ L-EF group; ▪ M-EF group; ▴ H-EF group; * P<0.05

Mentions: Neither organ bleeding nor death was found in any group throughout the experimental period. Either ALT or AST, the index of hepatocyte injury, did not significantly change from baseline among all the groups except moderate increase at 1 week in the CON group throughout the experimental period (Figure 2A–B). ON lesion was not found until week 2 post induction in each group. ON lesion was histopathologically characterized with trabecular bone containing considerable empty lacunae (Figure 3A, 3B and 3C). The ON Incidence was 93% (15/16) in the CON group, 56% (9/16) in the L-EF group, 13% (2/16) in the M-EF group and 6% (1/16) in the H-EF group, respectively. Fisher's exact probability test showed that the ON incidence in the L-EF, M-EF and H-EF group was significantly lower than that in the CON group (P<0.05 for all). The ON Incidence in the M-EF and H-EF group was significantly lower than that in the L-EF group (P<0.05 for both), whereas no difference in the ON Incidence was found between the M-EF and H-EF group (P>0.05). There was no significant difference in the ON Extent among the CON group (2.8±0.8), L-EF group (2.5±0.6), M-EF group (2.4±0.7) and H-EF group (2.6±0.5) (Figure 3D and 3E).


Constitutional flavonoids derived from Epimedium dose-dependently reduce incidence of steroid-associated osteonecrosis not via direct action by themselves on potential cellular targets.

Zhang G, Wang XL, Sheng H, Xie XH, He YX, Yao XS, Li ZR, Lee KM, He W, Leung KS, Qin L - PLoS ONE (2009)

Key characteristics for histopathological identification and histopathological data analysis.ON lesion was found with trabecular bone containing considerable empty lacunae and lack of marrow cells (B) when compared to normal bone (A). In ON+ rabbits, thrombi were predominantly found in small marrow vessels with lack of angiographic particles (C), and marrow was predominantly occupied by a numerous fat cells (B, C). (D) Incidence of ON in each group: CON (13/14, 93%), L-EF (9/16, 56%), M-EF (2/16, 13%), H-EF (1/16, 6%). (E) There was no significant difference in ON Extent among all the groups. (F) Thrombotic Vessel Counts, and (G) Fat Cell Area Fraction presented similarities in changing patter over time, i.e. either attenuated in the L-EF group or prevented in both the M-EF and H-EF group when compared to that in the CON group. Note: Arrow pointed particle was angiographic substance during microCT-based angiography (data not shown). • CON group; ⧫ L-EF group; ▪ M-EF group; ▴ H-EF group; * P<0.05
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Related In: Results  -  Collection

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pone-0006419-g003: Key characteristics for histopathological identification and histopathological data analysis.ON lesion was found with trabecular bone containing considerable empty lacunae and lack of marrow cells (B) when compared to normal bone (A). In ON+ rabbits, thrombi were predominantly found in small marrow vessels with lack of angiographic particles (C), and marrow was predominantly occupied by a numerous fat cells (B, C). (D) Incidence of ON in each group: CON (13/14, 93%), L-EF (9/16, 56%), M-EF (2/16, 13%), H-EF (1/16, 6%). (E) There was no significant difference in ON Extent among all the groups. (F) Thrombotic Vessel Counts, and (G) Fat Cell Area Fraction presented similarities in changing patter over time, i.e. either attenuated in the L-EF group or prevented in both the M-EF and H-EF group when compared to that in the CON group. Note: Arrow pointed particle was angiographic substance during microCT-based angiography (data not shown). • CON group; ⧫ L-EF group; ▪ M-EF group; ▴ H-EF group; * P<0.05
Mentions: Neither organ bleeding nor death was found in any group throughout the experimental period. Either ALT or AST, the index of hepatocyte injury, did not significantly change from baseline among all the groups except moderate increase at 1 week in the CON group throughout the experimental period (Figure 2A–B). ON lesion was not found until week 2 post induction in each group. ON lesion was histopathologically characterized with trabecular bone containing considerable empty lacunae (Figure 3A, 3B and 3C). The ON Incidence was 93% (15/16) in the CON group, 56% (9/16) in the L-EF group, 13% (2/16) in the M-EF group and 6% (1/16) in the H-EF group, respectively. Fisher's exact probability test showed that the ON incidence in the L-EF, M-EF and H-EF group was significantly lower than that in the CON group (P<0.05 for all). The ON Incidence in the M-EF and H-EF group was significantly lower than that in the L-EF group (P<0.05 for both), whereas no difference in the ON Incidence was found between the M-EF and H-EF group (P>0.05). There was no significant difference in the ON Extent among the CON group (2.8±0.8), L-EF group (2.5±0.6), M-EF group (2.4±0.7) and H-EF group (2.6±0.5) (Figure 3D and 3E).

Bottom Line: However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events.The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways.The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis.

View Article: PubMed Central - PubMed

Affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.

ABSTRACT
Intravascular-thrombosis and extravascular-lipid-deposit are the two key pathogenic events considered to interrupt intraosseous blood supply during development of steroid-associated osteonecrosis (ON). However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events. The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways. The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis. These findings encourage designing clinical trials to investigate potential of EF in prevention of steroid-associated ON.

Show MeSH
Related in: MedlinePlus