α2-Antiplasmin is involved in bone loss induced by ovariectomy in mice

Shiomi, Akihito; Kawao, Naoyuki; Yano, Masato; Okada, Kiyotaka; Tamura, Yukinori; Okumoto, Katsumi; Matsuo, Osamu; Akagi, Masao; Kaji, Hiroshi

doi:10.1016/j.bone.2015.06.009

Cited by 16 publications

(17 citation statements)

References 45 publications

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“…[9][10][11] On the other hand, α2AP is known to have various functions, such as cytokine production, cell growth, cell differentiation, and to be associated with angiogenesis, immune and inflammatory responses, tissue remodeling, fibrosis, brain functions, and bone formation. [12][13][14][15][16][17][18][19] The increased circulating levels of PAP and α2AP, and the impaired fibrinolysis have been reported in patients with SLE. 7,8 These findings suggest that α2AP may play a critical role in the development of SLE.…”

Section: Introductionmentioning

confidence: 99%

α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses

Kanno

Miyashita

Seishima

et al. 2020

Immunity Inflam & Disease

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Introduction: Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is a chronic autoimmune disease. However, the detailed mechanisms underlying this disorder have remained unclear. Alpha2-antiplasmin (α2AP) is known to perform various functions, such as plasmin inhibition and cytokine production, and to be associated with immune and inflammatory responses. Methods: We investigated the roles of α2AP in the pathogenesis of LN using a pristane-induced lupus mouse model. Results: The levels of plasmin-α2AP complex and α2AP were elevated in the lupus model mice. In addition, α2AP deficiency attenuated the pristaneinduced glomerular cell proliferation, mesangial matrix expansion, collagen production, fibrin deposition, immunoglobulin G deposition, and proinflammatory cytokine production in the model mice. We also showed that interferon-γ (IFN-γ), which is an essential inducer of LN, induced α2AP production through the c-Jun N-terminal kinase (JNK) pathway in fibroblasts. In addition, plasmin attenuated the IFN-γ-induced proinflammatory cytokine production through the AMPK pathway in macrophages, and α2AP eliminated these effects. Furthermore, we showed that α2AP induced proinflammatory cytokine production through the ERK1/2 and JNK pathways in macrophages. Conclusion: α2AP regulates the inflammatory responses through plasmin inhibition and proinflammatory cytokine production and is associated with the development of LN. Our findings may be used to develop a novel therapeutic approach for SLE.

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Section: Introductionmentioning

confidence: 99%

α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses

Kanno

Miyashita

Seishima

et al. 2020

Immunity Inflam & Disease

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“…It is unclear whether the reduction in osteoclast surface in iPAI‐1‐treated OVX mice is attributable to a direct effect on the osteoclasts or a secondary genetic effect. Plasmin inhibitors such as α2‐antiplasmin are involved in OVX‐induced bone loss in mice . Further, α2‐antiplasmin deficiency, along with interleukin (IL)‐1β, significantly prevents elevated bone resorption following OVX , and α2‐antiplasmin plays a role in OVX‐induced bone loss via a mechanism that depends in part on the production of IL‐1β .…”

Section: Discussionmentioning

confidence: 99%

“…Plasmin inhibitors such as α2‐antiplasmin are involved in OVX‐induced bone loss in mice . Further, α2‐antiplasmin deficiency, along with interleukin (IL)‐1β, significantly prevents elevated bone resorption following OVX , and α2‐antiplasmin plays a role in OVX‐induced bone loss via a mechanism that depends in part on the production of IL‐1β . As iPAI‐1 promotes plasmin activation like α2‐antiplasmin, some pro‐osteoclastogenesis factors might be downregulated by iPAI‐1 administration.…”

Section: Discussionmentioning

confidence: 99%

A small‐molecule PAI‐1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency‐induced osteoporosis model

et al. 2018

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Osteoporosis is a progressive bone disease caused by an imbalance between bone resorption and formation. Recently, plasminogen activator inhibitor‐1 (PAI‐1) was shown to play an important role in bone metabolism using PAI‐1‐deficient mice. In this study, we evaluated the therapeutic benefits of novel, orally available small‐molecule PAI‐1 inhibitor (iPAI‐1) in an estrogen deficiency‐induced osteoporosis model. Eight‐week‐old C57BL/6J female mice were divided into three groups: a sham + vehicle (Sham), ovariectomy + vehicle (OVX + v), and OVX + iPAI‐1 (OVX + i) group. iPAI‐1 was administered orally each day for 6 weeks starting the day after the operation. Six weeks of iPAI‐1 treatment prevented OVX‐induced trabecular bone loss in both the femoral bone and lumbar spine. Bone formation activity was significantly higher in the OVX + i group than in the OVX + v and Sham groups. Unexpectedly, OVX‐induced osteoclastogenesis was partially, but significantly reduced. Fluorescence‐activated cell sorting analyses indicated that the number of bone marrow stromal cells was higher in the OVX + i group than that in the OVX + v group. A colony‐forming unit‐osteoblast assay indicated enhanced mineralized nodule formation activity in bone marrow cells isolated from iPAI‐1‐treated animals. Bone marrow ablation analysis indicated that the remodeled trabecular bone volume was significantly higher in the iPAI‐1‐treated group than that in the control group. In conclusion, our results suggest PAI‐1 blockade via a small‐molecule inhibitor is a new therapeutic approach for the anabolic treatment of postmenopausal osteoporosis.

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“…Female WT and PAI-1 KO mice were randomly divided into four groups: WT/Sham ( n = 11), WT/ovariectomy (OVX) (n = 11), PAI-1 KO/Sham ( n = 10) and PAI-1 KO/OVX (n = 11). Seven-week-old female WT and PAI-1 KO mice were ovariectomized or sham-operated as previously described [ 16 ]. One week after the OVX or sham surgery, all mice received destabilization of the medial meniscus (DMM) surgery on the right knee due to induction of OA and sham surgery on the left knee.…”

Section: Methodsmentioning

confidence: 99%

Plasminogen activator inhibitor-1 deficiency enhances subchondral osteopenia after induction of osteoarthritis in mice

Moritake

Kawao

Okada

et al. 2017

BMC Musculoskelet Disord

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BackgroundSubchondral osteopenia is important for the pathophysiology of osteoarthritis (OA). Although previous studies suggest that plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is related to bone metabolism, its role in OA remains unknown. We therefore investigated the roles of PAI-1 in the subchondral bone in OA model mice.MethodsWild type (WT) and PAI-1-deficient (KO) mice were ovariectomized (OVX), and then destabilization of the medial meniscus (DMM) surgery was performed.ResultsDMM and OVX significantly decreased the trabecular bone mineral density of the subchondral bone evaluated by quantitative computed tomography in PAI-1 KO mice. The effects of OVX and/or PAI-1 deficiency on the OARSI score for the evaluation of the progression of knee degeneration were not significant. PAI-1 deficiency significantly augmented receptor activator nuclear factor κB ligand mRNA levels enhanced by IL-1β in mouse primary osteoblasts, although it did not affect osteoblast differentiation. Moreover, PAI-1 deficiency significantly increased osteoclast formation from mouse bone marrow cells.ConclusionWe showed that PAI-1 deficiency accelerates the subchondral osteopenia after induction of OA in mice. PAI-1 might suppress an enhancement of bone resorption and subsequent subchondral osteopenia after induction of OA in mice.

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α2-Antiplasmin is involved in bone loss induced by ovariectomy in mice

Cited by 16 publications

References 45 publications

α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses

α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses

A small‐molecule PAI‐1 inhibitor prevents bone loss by stimulating bone formation in a murine estrogen deficiency‐induced osteoporosis model

Plasminogen activator inhibitor-1 deficiency enhances subchondral osteopenia after induction of osteoarthritis in mice

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