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. 2022 Apr 7;28(13):1315-1328.
doi: 10.3748/wjg.v28.i13.1315.

Jianpi Qingchang Bushen decoction improves inflammatory response and metabolic bone disorder in inflammatory bowel disease-induced bone loss

Ya-Li Zhang  1 , Qian Chen  1 , Lie Zheng  2 , Zi-Wei Zhang  1 , Yu-Jun Chen  1 , Yan-Cheng Dai  3 , Zhi-Peng Tang  4
Affiliations

Jianpi Qingchang Bushen decoction improves inflammatory response and metabolic bone disorder in inflammatory bowel disease-induced bone loss

Ya-Li Zhang et al. World J Gastroenterol. .

Abstract

Background: Bone loss and osteoporosis are commonly described as extra-intestinal manifestations of inflammatory bowel disease (IBD). Jianpi Qingchang Bushen decoction (JQBD) is a prescription used in clinical practice. However, further studies are needed to determine whether JQBD regulates the receptor activator of nuclear factor kappa B (NF-κB) (RANK)/receptor activator of NF-κB ligand (RANKL)/ osteoprotegerin (OPG) pathways and could play a role in treating IBD-induced bone loss.

Aim: To evaluate the therapeutic effect of JQBD in IBD-induced bone loss and explore the underlying mechanisms.

Methods: An IBD-induced bone loss model was constructed by feeding 12 6-to-8-wk-old interleukin-10 (IL-10)-knockout mice with piroxicam for 10 d. The mice were randomly divided into model and JQBD groups. We used wild-type mice as a control. The JQBD group was administered the JQBD suspension for 2 wk by gavage, while the control and model groups were given normal saline at the corresponding time points. All mice were killed after the intervention. The effect of JQBD on body weight, disease activity index (DAI), and colon length was analyzed. Histopathological examination, colon ultrastructure observation, and micro-computed tomographic scanning of the lumbar vertebrae were performed. The gene expression of NF-κB, tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-8 in the colon was evaluated by real-time polymerase chain reaction. Colon samples were assessed by Western blot for the expression of RANKL, OPG, RANK, and NF-κB proteins.

Results: The model group lost body weight, had a shorter colon, and showed a dramatic increase in DAI score, whereas JQBD had protective and therapeutic effects. Treatment with JQBD significantly improved inflammatory cell infiltration and reduced crypt abscess and ulcer formation. Three-dimensional imaging of the vertebral centrum in the model group revealed a lower bone mass, loose trabeculae, and "rod-shaped" changes in the structure compared to the control group and JQBD groups. The bone volume/total volume ratio and bone mineral density were significantly lower in the model group than in the control group. JQBD intervention downregulated the NF-κB, TNF-α, IL-1β, IL-6, and IL-8 mRNA expression levels. The RANKL and OPG protein levels were also improved.

Conclusion: JQBD reduces inflammation of the colonic mucosa and inhibits activation of the RANK/ RANKL/OPG signaling pathway, thereby reducing osteoclast activation and bone resorption and improving bone metabolism.

Keywords: Bone metabolism; Inflammation; Inflammatory bowel disease; Jianpi Qingchang Bushen decoction; Osteoporosis.

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Conflict of interest statement

Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this study.

Figures

Figure 1
Figure 1
Gene detection results in F6-generation mice. A: Interleukin (IL)-10 conditional knockout; B: IL-10 knockout; C: Dppa3-cre.
Figure 2
Figure 2
Animal experimental flow and fecal occult blood test. A: An experimental bone loss inflammatory bowel disease model was induced by peroral administration of piroxicam for 10 d in interleukin-10-/- mice. Normal saline or Jianpi Qingchang Bushen decoction (JQBD; 16.5 g/kg/d) was given intragastrically to the control/model groups and JQBD group, respectively (n = 6, each); B: Fecal occult blood test of control and model groups: The control group was negative, and the model group was strongly positive for occult blood. JQBD: Jianpi Qingchang Bushen decoction Group.
Figure 3
Figure 3
General condition of the mice. A: Disease activity index scores gauged daily (n = 6 per group); B: Body weight measured daily (n = 6 per group); C and D: Colon length measurement and graph presenting the statistical analysis results. Data are presented as the mean ± SD. aP < 0.05; bP < 0.01; cP < 0.001 (n = 6 per group).
Figure 4
Figure 4
Histological evaluation of the colonic mucosa following hematoxylin and eosin staining (× 100) and ultrastructure of the colonic epithelium by transmission electron microscopy (× 6000). Arrows indicate goblet cells (a), crypts (b), inflammatory cells infiltration (c), epithelium surface erosion (d), and submucosal oedema (e). Control: Control group; Model: Model group; JQBD: Jianpi Qingchang Bushen decoction Group; Nu: Nucleus; Mi: Mitochondrial; ER: Endoplasmic Reticulum; rER: Rough endoplasmic reticulum; Mv: Microvillus.
Figure 5
Figure 5
Three-dimensional reconstruction of the lumbar spine trabecular structure in mice and micro-computed tomographic analyses of the lumbar vertebral metaphysis. Bone volume to total volume (BV/TV) ratio, Conn-Dens, trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), and bone mineral density (BMD) were obtained for all mice. A: Control; B: Model; C: JQBD; D: BV/TV; E: Conn-Dens; F: Trabecular number; G: Trabecular thickness; H: Trabecular separation; I: Bone mineral density. Control: Control group; Model: Model group; JQBD: Jianpi Qingchang Bushen decoction Group; BV/TV: Bone volume to total volume ratio; Conn-Dens: Connectivity-density; Tb.N: Trabecular number; Tb.Th: Trabecular thickness; Tb.Sp: Trabecular separation; BMD: Bone mineral density. Data are presented as the mean ± SD. aP < 0.05. (n = 6 per group).
Figure 6
Figure 6
Effect of Jianpi Qingchang Bushen decoction on nuclear factor-kappaB, tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-8 gene expression. The relative expression of these genes was quantified by real-time fluorescence quantitative polymerase chain reaction. A: NF-κB; B: TNF-α; C: IL-1β; D: IL-6; E: IL-8. Control: Control group; Model: Model group; JQBD: Jianpi Qingchang Bushen decoction Group; NF-κB: Nuclear factor-kappaB; TNF-α: Tumor necrosis factor-α; IL: Interleukin. Data are presented as the mean ± SD. aP < 0.05; bP < 0.01; cP < 0.001 (n = 3 per group).
Figure 7
Figure 7
Effect of Jianpi Qingchang Bushen decoction on receptor activator of nuclear factor κB ligand, osteoprotegerin, receptor activator of nuclear factor kappa B, and nuclear factor-kappaB protein expression. A: Protein expression quantified by Western blot; B: RANKL; C: OPG; D: RANK; E: NF-κB. Control: Control group; Model: Model group; RANK: Receptor activator of nuclear factor kappa B; RANKL: Receptor activator of nuclear factor κB ligand; JQBD: Jianpi Qingchang Bushen decoction Group. Data are presented as the mean ± SD. aP < 0.05; bP < 0.01; cP < 0.001 (n = 3 per group).
Figure 8
Figure 8
Possible mechanisms of bone loss in inflammatory bowel disease. IBD: Inflammatory bowel disease; OPG: Osteoprotegerin; RANK: Receptor activator of nuclear factor kappa B; RANKL: Receptor activator of nuclear factor κB ligand; JQBD: Jianpi Qingchang Bushen decoction Group.
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