Pravastatin Protects Against Avascular Necrosis of Femoral Head via Autophagy

Liao, Yun; Zhang, Ping; Yuan, Bo; Li, Ling; Bao, Shisan

doi:10.3389/fphys.2018.00307

Cited by 38 publications

(36 citation statements)

References 42 publications

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“…The migrated cells on the lower side of filter were then stained with 0.3% crystal violet in methanol and counted under a microscope. EPCs were generated by flushing bone marrow cells from 2‐month‐old C57/Bl6 mice in M199 media and seeded into Vitronectin‐coated 6‐well plate . Cells were validated by staining with DiI‐Ac‐LDL (Biomedical Technologies, Inc., BT 902).…”

Section: Methodsmentioning

confidence: 99%

Periarticular Mesenchymal Progenitors Initiate and Contribute to Secondary Ossification Center Formation During Mouse Long Bone Development

et al. 2019

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Long bone development involves the embryonic formation of a primary ossification center (POC) in the incipient diaphysis followed by postnatal development of a secondary ossification center (SOC) at each epiphysis. Studies have elucidated major basic mechanisms of POC development, but relatively little is known about SOC development. To gain insights into SOC formation, we used Col2-Cre Rosa-tdTomato (Col2/Tomato) reporter mice and found that their periarticular region contained numerous Tomato-positive lineage cells expressing much higher Tomato fluorescence (termed Tomato H ) than underlying epiphyseal chondrocytes (termed Tomato L ). With time, the Tomato H cells became evident at the SOC invagination site and cartilage canal, increased in number in the expanding SOC, and were present as mesenchymal lineage cells in the subchondral bone. These data were verified in two mouse lineage tracing models, Col2-CreER Rosa-tdTomato and Gli1-CreER Rosa-tdTomato. In vitro tests showed that the periarticular Tomato H cells from Col2/Tomato mice contained mesenchymal progenitors with multidifferentiation abilities. During canal initiation, the cells expressed vascular endothelial growth factor (VEGF) and migrated into epiphyseal cartilage ahead of individual or clusters of endothelial cells, suggesting a unique role in promoting vasculogenesis. Later during SOC expansion, chondrocytes in epiphyseal cartilage expressed VEGF, and angiogenic blood vessels preceded Tomato H cells. Gene expression analyses of microdissected samples revealed upregulation of MMPs in periarticular cells at the invagination site and suggested potential roles for novel kinase and growth factor signaling pathways in regulating SOC canal initiation. In summary, our data indicate that the periarticular region surrounding epiphyseal cartilage contains mesenchymal progenitors that initiate SOC development and form subchondral bone. STEM CELLS 2019;37:677-689 SIGNIFICANCE STATEMENTLong bone development involves the embryonic formation of a primary ossification center in the incipient diaphysis followed by postnatal development of secondary ossification centers (SOCs) at each epiphysis. In the present work, genetically modified fluorescent reporter mice were used to show a layer of highly fluorescent cells along the epiphyseal surface contain mesenchymal stem cells responsible for initiating SOC formation, recruiting surrounding vessels and establishing all mesenchymal lineage cells within this bone compartment. The finding reveals an important role of the periarticular region during skeletal development and highlights its potential use as a source of multipotent progenitor cells for therapeutic treatment.

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Section: Methodsmentioning

confidence: 99%

Periarticular Mesenchymal Progenitors Initiate and Contribute to Secondary Ossification Center Formation During Mouse Long Bone Development

et al. 2019

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“…Several signaling cascades, as reported, have been implicated in these beneficial roles of statins. In endothelial cells, statins could exert the proangiogenic effect by activating the PI3K/Akt pathway, attenuate the oxidative stress via modulating ERK1/2 pathway, and inhibit apoptosis via a PPAR alpha-dependent pathway 12,15,16. However, it remains to elucidate whether Prava, or other statins, protects against ischemia and necrosis on random skin flaps.…”

Section: Introductionmentioning

confidence: 99%

<p>Therapeutic potential of pravastatin for random skin flaps necrosis: involvement of promoting angiogenesis and inhibiting apoptosis and oxidative stress</p>

Lin¹,

Jia²,

Wang³

et al. 2019

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Background: Random skin flap is frequently used in plastic and reconstructive surgery, but its distal part often occurs ischemia and necrosis. Pravastatin (Prava) with bioactivities of pro-angiogenesis, anti-apoptosis and anti-oxidative stress, may be beneficial for flap survival. Materials and methods: A modified McFarlane flap model was performed in Sprague-Dawley rats. The animals were divided into the Control and Prava groups and treated as follows: the Prava group was injected intraperitoneally with 2 mg/kg Prava for consecutive 7 days, and the Control group received an equal volume of vehicle daily. On day 7, the necrosis skin flaps were observed, while visualization of blood flow below the tissue surface was performed by Laser Doppler blood flow imaging (LDBFI). Then animals were euthanized, and levels of angiogenesis, apoptosis and oxidative stress were analyzed. Results: Prava decreased necrosis and edema of skin flaps compared with the Control group, with more blood flow in the flap under LDBFI. Prava treatment increased the mean vessels density, elevated the expression levels of angiogenic proteins (matrix metallopeptidase 9, vascular endothelial growth factor, Cadherin5) and antioxidant proteins (superoxide dismutase 1 (SOD1), endothelial nitric oxide synthase, heme oxygenase), and decreased the expression of apoptotic factors (BAX, CYC, Caspase3). In addition, malondialdehyde content was reduced, and glutathione level and SOD activity were increased in the skin flaps after treatment with Prava. Conclusion: Prava promotes survival of random skin flap through induction of angiogenesis, and inhibition of apoptosis and oxidative stress.

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“…Moreover, Liao et al[ 22 ] reported that compared with the control group, the LC3-II/LC3-I ratio of dexamethasone group gradually decreased from 12 h (p<0.01) to 24 h (p<0.05), reaching the minimum at 48 h. They verified that autophagy was inhibited by dexamethasone treatment time-dependently. Furthermore, Luo et al[ 23 ] reviewed the role of autophagy in steroid-induced FHN.…”

Section: Discussionmentioning

confidence: 95%