Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling

Yan, Qingnan; Gao, Huanqing; Yao, Qing; Ling, Kun; Xiao, Guozhi

doi:10.1016/j.jbc.2022.101639

Cited by 14 publications

(14 citation statements)

References 32 publications

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“…For in vitro knockdown of Kindlin-2 expression, ATDC5 cells were transfected with Kindlin-2-targeting siRNA as previously described (Invitrogen, Cat# 13778075) as previously described. 51 ATDC5 cells transfected with a negative control siRNA were used as control group. Protein extracts were collected 48 h after siRNA transfection and examined by western blotting.…”

Section: Methodsmentioning

confidence: 99%

Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Lai

Zheng

et al. 2022

Int J Oral Sci

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The progressive destruction of condylar cartilage is a hallmark of the temporomandibular joint (TMJ) osteoarthritis (OA); however, its mechanism is incompletely understood. Here, we show that Kindlin-2, a key focal adhesion protein, is strongly detected in cells of mandibular condylar cartilage in mice. We find that genetic ablation of Kindlin-2 in aggrecan-expressing condylar chondrocytes induces multiple spontaneous osteoarthritic lesions, including progressive cartilage loss and deformation, surface fissures, and ectopic cartilage and bone formation in TMJ. Kindlin-2 loss significantly downregulates the expression of aggrecan, Col2a1 and Proteoglycan 4 (Prg4), all anabolic extracellular matrix proteins, and promotes catabolic metabolism in TMJ cartilage by inducing expression of Runx2 and Mmp13 in condylar chondrocytes. Kindlin-2 loss decreases TMJ chondrocyte proliferation in condylar cartilages. Furthermore, Kindlin-2 loss promotes the release of cytochrome c as well as caspase 3 activation, and accelerates chondrocyte apoptosis in vitro and TMJ. Collectively, these findings reveal a crucial role of Kindlin-2 in condylar chondrocytes to maintain TMJ homeostasis.

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Section: Methodsmentioning

confidence: 99%

Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Lai

Zheng

et al. 2022

Int J Oral Sci

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“…Primary bone marrow stromal cells (BMSC) were isolated from femurs of 3-month-old male mice as previously described (Yan, Gao, Yao, Ling, & Xiao, 2022). Briefly, bone marrow cells were cultured on 60-mm cell culture dishes in α-MEM (Hyclone, USA) containing 15% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…Primary bone marrow stromal cells (BMSC) were isolated from femurs of 3-month-old male mice as previously described (Yan, Gao, Yao, Ling, & Xiao, 2022).…”

Section: Bmsc Culturementioning

confidence: 99%

“…Wu, Cao, & Xiao, 2021;X. Wu et al, 2022), heart (Liang, Sun, & Chen, 2009;Qi et al, 2019;Zhang et al, 2016), kidney (Lausecker et al, 2018;Sun et al, 2017;Wei et al, 2013), pancreatic islets (Zhu et al, 2020), adipose tissue (H. Gao et al, 2019), small intestine (He et al, 2020), testicle (Chi et al, 2021), and liver(H. Gao et al, 2021;H. Gao et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Focal adhesion protein vinculin inhibits Mef2c-driven sclerostin expression in osteocytes to promote bone formation in mice

Wang

Huang

Lin

et al. 2022

Preprint

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The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Deleting vinculin using the mouse 10-kb Dmp1-Cre transgenic mice causes a severe osteopenia in both young and aged mice by impairing osteoblast function without affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. At the molecular level, vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of the Sost gene, which encodes sclerostin. Vinculin interacts with Mef2c and vinculin loss enhances Mef2c nuclear translocation and binding to the Sost enhancer ECR5 to promote sclerostin production in osteocytes. Deleting Sost expression reverses the osteopenic phenotypes caused by vinculin loss in mice. We demonstrate that estrogen is a major regulator of vinculin expression in osteocytes and that more importantly vinculin loss mediates estrogen deficiency induction of bone loss in mice. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.

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“…Devemos considerar ainda a complexidade da diferenciação osteoblástica, onde muitos genes das vias avaliadas participam de funções biológicas diversas, tais como proliferação, diferenciação e migração celular, desenvolvimento embrionário e esquelético, formação óssea, remodelação e reparo tecidual, defesa do hospedeiro e hemostasia. (YAN et al, 2022;YU et al, 2021;COSTANTINI et al, 2018;PERSSON et al, 2019;HENDRICKX et al, 2017;DOCHEVA et al, 2014;LIU et al, 2013;MULLIN et al, 2013;KATOH;KATOH, 2007) (HUAMAN et al 2019;WANG et al, 2019). Além disso, assim como apresentado aqui, estudos anteriores utilizando o mesmo modelo experimental mostraram que a utilização de células alógenas foi segura e induziu a formação de tecido ósseo após injeção nos defeitos (ADOLPHO et al, 2022;FREITAS et al, 2019a;FREITAS et al, 2019b;FREITAS et al, 2017).…”

Section: Avaliação Da Expressão Gênica De Marcadores Osteoblásticos P...unclassified

Efeitos das interações entre células-tronco mesenquimais de ratos saudáveis e com osteoporose, diabetes mellitus ou hipertensão arterial na diferenciação osteoblástica e na regeneração de defeitos ósseos

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as ORX-MSC não prejudicaram a diferenciação de SD-MSC, as DM-MSC prejudicam pouco e as HA-MSC prejudicam ainda mais essa diferenciação. Nessas interações houve modulação de genes das vias de sinalização das BMP, WNT e ITG em diferentes graus. As SD-MSC permanecerem nos defeitos de todas as doenças e a terapia celular resultou em maior formação óssea comparada à injeção de PBS nos defeitos de animais com osteoporose e HA, mas não com DM. Os resultados desse estudo são relevantes para o desenvolvimento de terapia celular com vistas à regeneração do tecido ósseo em condições adversas como a osteoporose, DM ou HA.

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Loss of phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c) in mesenchymal stem cells leads to osteopenia by impairing bone remodeling

Cited by 14 publications

References 32 publications

Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Kindlin-2 loss in condylar chondrocytes causes spontaneous osteoarthritic lesions in the temporomandibular joint in mice

Focal adhesion protein vinculin inhibits Mef2c-driven sclerostin expression in osteocytes to promote bone formation in mice

Efeitos das interações entre células-tronco mesenquimais de ratos saudáveis e com osteoporose, diabetes mellitus ou hipertensão arterial na diferenciação osteoblástica e na regeneração de defeitos ósseos

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