Dataset Information

Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice.

ABSTRACT: Postmenopausal osteoporosis is characterized by excess osteoclastogenesis which leads to net bone loss and brittle fractures. Studies have demonstrated that estrogen deficiency-associated bone loss is microbiota-dependent and could be prevented by probiotics and prebiotics. In this study, we report that orally administered lactulose (20 g/kg, 6 weeks) orally administered significantly inhibited osteoclastogenesis, bone resorption, and prevented ovariectomy (OVX)-induced bone loss in mice. Lactulose increased intestinal Claudin 2, 3 and 15, compared to the OVX group, and lowered pro-osteoclastogenic cytokines levels including tumor necrosis factor-?, interleukin(IL)-6, receptor activator of nuclear factor kappa-? ligand (RANKL), and IL-17 as well as increased the anti-inflammatory cytokine IL-10 in the intestine, peripheral blood, and bone marrow. Lactulose significantly preserved the number of Foxp3+ Treg cells in the intestines compared with that in OVX mice. Lactulose altered the composition of intestinal microbiota measured by 16s rDNA sequencing and increased intestinal and serum short-chain fatty acids (SCFAs) levels including acetate, propionate and butyrate which were decreased in OVX mice as measured by gas chromatography. Oral administration of lactulose for 2 weeks significantly lowered the level of bone resorption marker C-telopeptide of type 1 collagen-1 in healthy male young volunteers (aging 20-25 years). In conclusion, lactulose inhibited osteoclastogenesis and bone resorption by altering the intestinal microbiota and increasing SCFAs. Lactulose could serve as an ideal therapeutic agent for postmenopausal osteoporosis.

SUBMITTER: Chen X

PROVIDER: S-EPMC7220299 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice.

Chen Xiao X Zhang Zheng Z Hu Yan Y Cui Jin J Zhi Xin X Li Xiaoqun X Jiang Hao H Wang Yao Y Gu Zhengrong Z Qiu Zili Z Dong Xin X Li Yuhong Y Su Jiacan J

Aging and disease 20200509 3

Postmenopausal osteoporosis is characterized by excess osteoclastogenesis which leads to net bone loss and brittle fractures. Studies have demonstrated that estrogen deficiency-associated bone loss is microbiota-dependent and could be prevented by probiotics and prebiotics. In this study, we report that orally administered lactulose (20 g/kg, 6 weeks) orally administered significantly inhibited osteoclastogenesis, bone resorption, and prevented ovariectomy (OVX)-induced bone loss in mice. Lactul ...[more]

PMID: 32489707

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Project description:Postmenopausal osteoporosis (PMOP) is a severe health issue faced by postmenopausal women. microRNA-128 (miR-128) is associated with aging, inflammatory signaling, and inflammatory diseases, such as PMOP. It has also been reported to modulate in vitro osteogenic/adipogenic differentiation. However, its function in osteoclast formation is unknown. Methods: First, the expression of miR-128 and nuclear factor of activated T cells 1 (Nfatc1, bone resorption master marker) was investigated in bone tissues derived from PMOP patients, while their correlation to each other was also investigated. The levels of miR-128 and Nfatc1 in bone specimens and bone marrow-derived macrophages (BMMs) from mice subjected to ovariectomy (OVX) were also assayed. Next, we employed mice BMMs modified for overexpression and inhibition of miR-128 levels to determine its effect on osteoclast differentiation. Moreover, we generated osteoclastic miR-128 conditional knockout (miR-128Oc-/- ) mice and isolated miR-128 deletion-BMMs to observe its biological function on bone phenotype and osteoclastogenesis in vivo, respectively. The miR-128Oc-/- BMMs were used to explore the downstream regulatory mechanisms using pull-down, luciferase reporter, and western-blotting assays. Finally, the impact of miR-128 deficiency on OVX-induced bone loss in mice was evaluated. Results: The miR-128 level was found to be positively correlated with the increase in Nfatc1 level in mouse/human bone specimens and mouse primary BMMs. In vitro experiments demonstrated miR-128 levels that were dependent on activity of osteoclast differentiation and miR-128 overexpression or inhibition in BMMs significantly increased or decreased osteoclastogenesis, respectively. In vivo, we revealed that osteoclastic miR-128 deletion remarkedly increased bone mass through the inhibition of osteoclastogenesis. Mechanistically, we identified sirtuin 1 (SIRT1) as the direct target of miR-128 at the post-transcriptional level during osteoclast differentiation. Increased levels of SIRT1 reduced nuclear factor ?B (NF-?B) activity by decreasing the level of acetylation of Lysine 310, as well as inhibiting tumor necrosis factor-? (Tnf-?) and interleukin 1 (IL-1) expressions. Lastly, osteoclastic deletion of miR-128 significantly suppressed OVX-triggered osteoclastogenesis and exerted a protective effect against bone loss in mice. Conclusions: Our findings reveal a critical mechanism for osteoclastogenesis that is mediated by the miR-128/SIRT1/NF-?B signaling axis, highlighting a possible avenue for the further exploration of diagnostic and therapeutic target molecules in PMOP.

Dataset Information

Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice.

Publications

Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice.

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