Inhibition of GSK3β Stimulates BMP Signaling and Decreases <i>SOST</i> Expression Which Results in Enhanced Osteoblast Differentiation

Schoeman, Monique A.E.; Moester, M. J. C.; Oostlander, A.E.; Kaijzel, Eric L.; Valstar, Edward R.; Nelissen, Rob G H H; Löwik, Clemens W.G.M.; Rooij, Karien E. de

doi:10.1002/jcb.25241

Cited by 17 publications

(17 citation statements)

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“…We found that CXCL13 was higher in treatment group than in the other two groups. ALP, the alkaline phosphatase, was regarded as the early marker of osteoblast phenotype and differentiation [37,38]. In this study, the increase rate of ALP was significantly lower in diabetic group than in the other two groups at various time points, suggesting a worse osteoblast differentiation in the diabetic group.…”

Section: Discussionmentioning

confidence: 51%

Effects of Transplanting Bone Marrow Stromal Cells Transfected with CXCL13 on Fracture Healing of Diabetic Rats

Jiang

Wang

Meng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetic fracture have poor treatment and serious complications. Therefore, how to treat diabetic fracture is receiving increasing attention. This study aimed to investigate the effects of transplanting CXCL13-stimulated bone marrow stromal cells (BMSCs) on the fracture healing in diabetic rats. Methods: In vitro, RT-PCR was employed to examine the expression of CXCL13 in BMSCs in high glucose environment. MTT assay and apoptosis assay were utilized to determine the effects of CXCL13 overexpression on the proliferation and apoptosis of BMSCs respectively. ALP staining was applied to detect the ALP activity. In vivo, CXCL13-stimulated BMSCs were transplanted into the fracture sites of diabetic rats. At the 1 st week, 2 nd weeks, 4 th week and 6 th week after the operation, bone mineral density (BMD) and callus area measurement, ELISA detection, and HE staining were performed to evaluate the fracture healing. Results: Low BMD and less area of callus in diabetic rats showed that the recovery after fracture was worse in diabetic rats than in non-diabetic rats. Meanwhile, the expression of CXCL13 in serum was lower in diabetic rats than in non-diabetic rats. Overexpression of CXCL13 promoted the proliferation of BMSCs in vitro high glucose environment. After BMSCs transfected with CXCL13 being transplanted into the fracture sites of diabetic rats, it was found that the fracture healing was enhanced and ALP expression in serum became higher. HE staining results further verified the effects of transplantation of BMSCs transfected with CXCL13 on fracture healing in diabetic rats. Conclusion: These finding indicated that CXCL13 may play a critical role in the process of fracture healing, which could provide a deeper insight into molecular targets for the fracture healing in diabetic people.

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Section: Discussionmentioning

confidence: 51%

Effects of Transplanting Bone Marrow Stromal Cells Transfected with CXCL13 on Fracture Healing of Diabetic Rats

Jiang

Wang

Meng

et al. 2018

Cell Physiol Biochem

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“…BMP-2-induced up-regulation of SOST has also been shown by a number of studies [Sutherland et al, 2004, Yu et al, 2011bSchoeman et al, 2015]. Although SOST is considered to be an antagonist of canonical Wnt-signaling in the first line, Sutherland et al [2004] and others [Schoeman et al, 2015] could show that BMP-4 as well as BMP-2 induced SOST expression.…”

Section: Discussionmentioning

confidence: 69%

“…Although SOST is considered to be an antagonist of canonical Wnt-signaling in the first line, Sutherland et al [2004] and others [Schoeman et al, 2015] could show that BMP-4 as well as BMP-2 induced SOST expression. The negative effects of BMP-4-induced SOST could be inhibited by addition of low doses of glycogen synthase kinase (GSK) 3b inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…We chose UMR-106 cells that constitutively express SOST and secrete sclerostin in an amount that is analytically well assessable and similar to the expression in osteocytes [Yu et al, 2011b]. Similarly, Saos-2 cells constitutively express SOST and have the advantage of being of human origin; however, the secreted amounts of sclerostin are quite low, thus causing problems in ELISA detection [Schoeman et al, 2015].…”

Section: Discussionmentioning

confidence: 99%

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Rat Osteosarcoma Cells as a Therapeutic Target Model for Osteoregeneration via Sclerostin Knockdown

Sedaghati

Jahroomishirazi²,

Starke

et al. 2016

Cells Tissues Organs

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There are various conceptually different strategies to improve bone regeneration and to treat osteoporosis, each with distinct inherent advantages and disadvantages. The use of RNA interference strategies to suppress the biological action of catabolic factors or antagonists of osteogenic proteins is promising, and such strategies can be applied locally. They are comparably inexpensive and do not suffer from stability problems as protein-based approaches. In this study, we focus on sclerostin, encoded by the SOST gene, a key regulator of bone formation and remodeling. Sclerostin is expressed by mature osteocytes but also by late osteogenically differentiated cells. Thus, it is difficult and requires long-term cultures to investigate the effects of SOST silencing on the expression of osteogenic markers using primary cells. We, therefore, selected a rat osteosarcoma cell line, UMR-106, that has been shown to express SOST and secrete sclerostin in a comparable fashion as late osteoblasts and osteocytes. We investigated the effects of differentiating supplements on SOST expression and sclerostin secretion in UMR-106 cells and found that addition of 100 ng/ml of bone morphogenetic protein (BMP)-2 strongly induced sclerostin secretion, whereas dexamethasone inhibited secretion. Effects of silencing SOST in UMR-106 cells cultured in various differentiation media including BMP-2 and/or dexamethasone were determined next with the aim to find promising test conditions for a readout system for the evaluation of future small interfering RNA release formulations for local induction of bone formation. We found a direct correlation between attenuated SOST expression and an increase in the osteogenic potential of UMR-106 cells. The combination of SOST silencing and BMP-2 could synergistically improve osteogenic factors. A lowered proliferation rate in silenced groups may indicate a faster switch to differentiation.

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“…BMP‐2 is even used in clinical practice for accelerated healing of fractures and for spinal fusions 30, 34. In our recent study using the murine cell‐line KS483, a combination of BMP‐4 and GIN (a stimulator of Wnt‐signalling) was found to enhance mineralization and decrease the expression of Sclerostin (an inhibitor of bone formation) compared to BMP‐4 alone 35. Therefore, we also stimulated cells with OM supplemented with either GIN or a combination of GIN and BMP‐2 or BMP‐6.…”

Section: Discussionmentioning

confidence: 99%

Peri-prosthetic tissue cells show osteogenic capacity to differentiate into the osteoblastic lineage

et al. 2017

Self Cite

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During the process of aseptic loosening of prostheses, particulate wear debris induces a continuous inflammatory‐like response resulting in the formation of a layer of fibrous peri‐prosthetic tissue at the bone‐prosthesis interface. The current treatment for loosening is revision surgery which is associated with a high‐morbidity rate, especially in old patients. Therefore, less invasive alternatives are necessary. One approach could be to re‐establish osseointegration of the prosthesis by inducing osteoblast differentiation in the peri‐prosthetic tissue. Therefore, the aim of this study was to investigate the capacity of peri‐prosthetic tissue cells to differentiate into the osteoblast lineage. Cells isolated from peri‐prosthetic tissue samples (n = 22)−obtained during revision surgeries−were cultured under normal and several osteogenic culture conditions. Osteogenic differentiation was assessed by measurement of Alkaline Phosphatse (ALP), mineralization of the matrix and expression of several osteogenic genes. Cells cultured in osteogenic medium showed a significant increase in ALP staining (p = 0.024), mineralization of the matrix (p < 0.001) and ALP gene expression (p = 0.014) compared to normal culture medium. Addition of bone morphogenetic proteins (BMPs), a specific GSK3β inhibitor (GIN) or a combination of BMP and GIN to osteogenic medium could not increase ALP staining, mineralization, and ALP gene expression. In one donor, addition of GIN was required to induce mineralization of the matrix. Overall, we observed a high‐inter‐donor variability in response to osteogenic stimuli. In conclusion, peri‐prosthetic tissue cells, cultured under osteogenic conditions, can produce alkaline phosphatase and mineralized matrix, and therefore show characteristics of differentiation into the osteoblastic lineage. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1732–1742, 2017.

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Inhibition of GSK3β Stimulates BMP Signaling and Decreases SOST Expression Which Results in Enhanced Osteoblast Differentiation

Cited by 17 publications

References 50 publications

Effects of Transplanting Bone Marrow Stromal Cells Transfected with CXCL13 on Fracture Healing of Diabetic Rats

Effects of Transplanting Bone Marrow Stromal Cells Transfected with CXCL13 on Fracture Healing of Diabetic Rats

Rat Osteosarcoma Cells as a Therapeutic Target Model for Osteoregeneration via Sclerostin Knockdown

Peri-prosthetic tissue cells show osteogenic capacity to differentiate into the osteoblastic lineage

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