Omentin-1 prevents inflammation-induced ost

INTRODUCTION

Bone remodeling is a lifelong process in vertebrates that relies on the balance between bone formation by osteoblasts and bone resorption by –3When the balance is disrupted,as is seen in chronic inflammatory diseases,such as rheumatoid arthritis and ankylosing spondylitis,abnormal bone loss and osteoporotic fractures often have reported that increases in the pro-inflammatory cytokines during chronic inflammation make an important contribution to bone loss by promoting osteoclast differentiation and/or inhibiting osteoblast maturation and ,4Thus,strategies designed to inhibit pro-inflammatory activities hold promise in promoting bone regeneration and preventing inflammation-induced osteoporosis.

Omentin-1,also referred to as intelectin-1(ITLN1),is a novel adipocytokine that is highly expressed in human visceral fat tissue and in mouse small protein is also highly abundant in plasma and circulating omentin-1 concentration has been found to be inversely correlated with the levels of proinflammatory factors,such as interleukin(IL)-6 and tumor necrosis factor-alpha (TNF-α)in individuals with impaired glucose regulation and chronic artery –6Recently,it has been reported that omentin-1 can inhibit pulmonary inflammation and endothelial injury after lipopolysaccharide(LPS)-induced acute respiratory distress syndrome(ARDS)in ,omentin-1 can attenuate atherosclerotic lesion formation in apolipoprotein E-deficient mice by reducing the inflammatory response of ,up to now,few studies have investigated the role of omentin-1 in inflammation-induced osteoporosis.

Previously,we demonstrated that omentin-1 could inhibit osteoclast differentiation in vitro via an indirect mechanism by stimulating the production of osteoprotegerin(OPG)and reducing the secretion of receptor activator for nuclear factorκB ligand(RANKL)in also determined in vivo that intravenous administration of adenoviral-delivered omentin-1 could prevent bone loss and enhance bone strength in ovariectomy-induced osteoporotic mice,9as well as in OPG-deficient upon these evidences outlined above,we hypothesized that omentin-1 might have inhibitory effects on inflammation-induced osteoporosis,as it may target both the bone metabolism and the inflammatory process.

In this study,we firstly generated global omentin-1 knockout(omentin-1-/-)mice for determining the role of omentin-1 in inflammation and bone loss.We also assessed the effects of recombinant omentin-1 on the TNF-α-induced inflammatory responses of macrophages,as well as on the activated macrophages-secreted factors-mediated regulation of osteoblast differentiation and osteoclast formation in ,we explored the therapeutic potential of adenovirus-mediated delivery of omentin-1 in a mouse model of inflammationinduced study aimed to uncover the role of omentin-1 in inflammatory osteoporosis and to preliminarily elucidate the mechanism underlying this process.

RESULTS

Omentin-1 depletion induces inflammatory bone loss-like phenotypes in vivo

To con firm the role of omentin-1 in inflammation and bone loss,we generated omentin-1-/-mice and characterized the knockout mice by DNA sequencing analysis(Fig.1a)and western blotting(Fig.1b).The results revealed that a base(A)was successfully inserted into the sequence of omentin-1 gene and caused a depletion of omentin-1 protein in small intestines(the organ showing the highest expression of omentin-1 in mice11–12)of omentin-1-/-mice compared with their wild-type then evaluated whether omentin-1 deficiency resulted in dysregulated revealed a drastic increase in the areas positively stained for the pro-inflammatory mediators,including IL-1β,IL-6,and TNF-α in the bone tissue of omentin-1-/-mice when compared with wild-type mice(Fig.1c–h).Consistently,omentin-1 depletion also caused a remarkable increase in serum concentrations of the IL-1α,IL-6,and TNF-α,as determined by enzyme-linked immunosorbent assay(ELISA)(Fig.1i–k).Paradoxically,we found that the level of IL-10,an anti-inflammatory cytokine that can suppress osteoclastogenesis and bone resorption,13–14was also markedly elevated in omentin-1-/-mice compared to the control mice(Fig.1l),indicating that omentin-1 depletion leads to dysregulated inflammatory responses in mice.

Subsequently,microcomputed tomography(μCT)scanning was carried out to evaluate the impact of omentin-1 deficiency on bone mass and microarchitecture in mice.As shown in Fig.2a,omentin-1 depletion caused a significant trabecular bone loss compared to wild-type quantitative analysis determined that omentin-1-/-mice displayed remarkably reduced trabecular bone volume fraction,thickness,and number,and increased trabecular separation than that in wild-type mice(Fig.2b–e).The periosteal perimeter of femoral diaphysis in omentin-1-/-mice were also much lower than that of wild-type mice(Fig.2a,f).Cortical bone thickness was also reduced in omentin-1-/-mice compared to wild-type mice,but the difference was not statistically significant(Fig.2a,g).Immunohistochemical staining and ELISA assay for osteocalcin(OCN),a marker expressed during osteogenic differentiation and mineralization,15–16revealed that osteogenic responses in omentin-1-/-mice were markedly decreased compared to wild-type mice(Fig.2h–j).However,osteoclast activities were dramatically enhanced after omentin-1 depletion,as evidenced by tartrate-resistant acid phosphatase(TRAP)staining on bone tissue sections and ELISA test for the bone resorption marker C-terminal telopeptides of type Icollagen(CTX-I)in serum(Fig.2k–m).We also asked whether omentin-1 deficiency affected the proliferation of osteoblast precursors and osteoclast progenitors by colony-forming unit-fibroblast(CFU-F)and colony-forming units-granulocyte/macrophage(CFU-GM) results revealed that bone marrow cells from omentin-1-/-mice formed much lower numbers of CFU-Fs and higher numbers of CFU-GMs than that in wild-type mice(Supplementary Figure 1),indicating that depletion of omentin-1 impairs the proliferation of osteoblast precursors and enhances the amplification of osteoclast data suggest that omentin-1 is required for maintaining normal bone metabolism.

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