The Bone-specific Expression of Runx2 Oscillates during the Cell Cycle to Support a G1-related Antiproliferative Function in Osteoblasts

Galindo, Mario; Pratap, Jitesh; Young, Daniel W.; Hovhannisyan, Hayk; Im, Hee Jeong; Choi, Je Yong; Lian, Jane B.; Stein, Janet L.; Wijnen, André J. van

doi:10.1074/jbc.m413665200

Cited by 224 publications

(270 citation statements)

References 78 publications

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“…However, RUNX2 has been described as a suppressor of osteoblast proliferation, and RUNX2 expression is regulated during the cell cycle. (7,10) Moreover, RUNX2 levels were upregulated by growth factor depletion and downregulated on cell cycle entry during active proliferation in response to growth factors. (7) Our previous work has shown that depending on the percentage of FCS in the culture medium, transfection of SaOs-2 cells with a dominant-negative form of RUNX2 increases the proliferation rate (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

“…Galindo and colleagues (10) observed that the growth-suppressing activity of RUNX2 in immature MC3T3 cells was controlled by cell cycle modulation. RUNX2 oscillates from a peak level during early G 1 to a trough during early S and M phases.…”

Section: Discussionmentioning

confidence: 99%

“…RUNX2 oscillates from a peak level during early G 1 to a trough during early S and M phases. (10) Kilbey and colleagues (18) demonstrated that the aberrant behavior of RUNX2 À/À cells in primary murine embryonic fibroblasts was associated with elevated cyclin expression. Our present results showed that inhibition of RUNX2 in hMSCs had no significant effect on levels of cyclin D1 but induced a strong increase in cyclins E1, A1, and B1.…”

Section: Discussionmentioning

confidence: 99%

“…(7,10) However, the RUNX genes have paradoxical roles in cancer, where they can function either as dominant oncogenes or as tumor suppressors based on the exact context. (48) In this study we present a novel mechanism of growth inhibition by RUNX2.…”

Section: Discussionmentioning

confidence: 99%

“…(7) The involvement of RUNX2 as a regulator of osteoblast proliferation also was consistent with data obtained in other biologic contexts. (8)(9)(10)(11) More recently, Zaidi and colleagues (12) proposed that RUNX2 functions as a tumor suppressor in primary diploid osteoblasts, whereas Eliseev and colleagues (13) suggested that RUNX2 acts as a proapoptotic factor.…”

Section: Introductionmentioning

confidence: 99%

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TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor a (TNF-a) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-a affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-a and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-a's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. ß

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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Extracellular Vesicle Clicking on Osteoimplants Through Biomimetic Molecular Adhesion Enables Immune‐Enhanced Osseointegration in Diabetics

Ge,

Wang,

Wang

et al. 2024

Adv Funct Materials

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Extracellular vesicles (EVs) derived from differentiating induced stem cells maintain their original stemness and differentiating trends and possess strong immunoregulatory capability. Biomaterials equipped with EVs are very promising in regenerative medicine. However, surface EV‐decoration on osteoimplants remains a challenge, due to the complexity of traditional molecular conjugations and the fragility of EVs. Here, mussel‐like molecular adhesion is combined with bioorthogonal click conjugation to introduce EVs on titanium (Ti) implants. The biomimetic adhesion and clickable molecular linkage allow mild and stable tethering of pre‐osteogenic mesenchymal stem cell (MSC)‐derived EVs on Ti implants. EV‐decorated implants exhibit significantly enhanced osseointegration on the bone‐implant surface under diabetic conditions, promoting increased expression of osteogenic genes. Modified surfaces impelled phenotypic alterations in macrophage polarization via multi‐pathway regulation, decreasing proinflammatory M1 macrophage formation, which can lead to the promotion of surface osteogenesis. On Ti rods implanted in a diabetic rat model, EV coating inhibited M1macrophages around the prosthesis, resulting in satisfactory long‐term osseointegration. This study offers a new perspective to represent a simple and effective means for surface EV decoration, providing an osteoimmunomodulatory effect to enhance the diabetic osseointegration of implants.

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3D Niche‐Inspired Scaffolds as a Stem Cell Delivery System for the Regeneration of the Osteochondral Interface

Camarero‐Espinosa,

Beeren,

Liu

et al. 2024

Advanced Materials

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The regeneration of the osteochondral unit represents a challenge due to the distinct cartilage and bonny phases present within. Current strategies focus on the development of multi‐phasic scaffolds that recapitulate features of this complex unit and promote the differentiation of implanted bone‐marrow derived stem cells (BMSCs). In doing so, challenges remain from the loss of stemness during in vitro expansion of the cells and the low control over the stem cell activity at the interface with scaffolds in vitro and in vivo. Here, we developed scaffolds inspired by the bone marrow niche that can recapitulate the natural healing process after injury. The construct comprises an internal depot of quiescent BMSCs, mimicking the bone marrow cavity, and an electrospun capsule that “activates” the cells to migrate into an outer “differentiation‐inducing” 3D printed unit functionalized with TGF‐β and BMP‐2 peptides. In vitro, niche‐inspired scaffolds retained a depot of non‐proliferative cells capable of migrating and proliferating through the electrospun capsule. Invasion of the 3D printed cavity resulted in location‐specific cell differentiation, mineralization, secretion of ALP and GAGs, and genetic upregulation of collagen II and collagen I. In vivo, niche‐inspired scaffolds were biocompatible, promoted tissue formation in rat subcutaneous models, and regeneration of the osteochondral unit in rabbit defect models.This article is protected by copyright. All rights reserved

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The Bone-specific Expression of Runx2 Oscillates during the Cell Cycle to Support a G1-related Antiproliferative Function in Osteoblasts

Cited by 224 publications

References 78 publications

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Extracellular Vesicle Clicking on Osteoimplants Through Biomimetic Molecular Adhesion Enables Immune‐Enhanced Osseointegration in Diabetics

3D Niche‐Inspired Scaffolds as a Stem Cell Delivery System for the Regeneration of the Osteochondral Interface

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