The Roles of Bone Morphogenetic Proteins and Their Signaling in the Osteogenesis of Adipose-Derived Stem Cells

Zhang, Xiao; Guo, Jing; Zhou, Yongsheng; Wu, Gang

doi:10.1089/ten.teb.2013.0204

Cited by 69 publications

(75 citation statements)

References 97 publications

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“…BMP2 has been extensively studied in MSC biology in the context of osteogenesis or osteoblastic differentiation [20]. BMP2 signaling is osteogenic for MSCs cultured on a stiff surface, but not osteogenic on a soft elasticity surface due to a decrease in R-Smad phosphorylation and subsequent nuclear translocation [42,43].…”

Section: Discussionmentioning

confidence: 99%

“…1). Although physiological roles of BMP2 in MSCs have been extensively studied in the context of osteogenic differentiation [20], other roles of BMP2 signaling have not been investigated.…”

Section: Bmp2 Treatment Strongly Reduces Proinflammatory and Anti-infmentioning

confidence: 99%

“…Although the role of BMP2 has been studied extensively in MSC biology in the context of osteogenesis or osteoblastic differentiation [20], the exact role of BMP2 signaling in MSC spheroids remains unknown. Because of strong BMP2 induction upon formation of MSC spheroids and the key role of BMP signaling in blastema formation, we hypothesized that BMP2 signaling plays a regulatory role in MSC spheroids.…”

Section: Introductionmentioning

confidence: 99%

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Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Cesarz

Funnell

Guan

et al. 2016

Stem Cells and Development

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Cell therapy with adult mesenchymal stem cells (MSCs) is a promising approach to regenerative medicine and autoimmune diseases. There are various approaches to improve the efficacy of MSC-based therapeutics, and MSC preparation as spheroidal aggregates, or MSC spheroids, is a novel preparatory and delivery method. Spheroid formation induces a dramatic change in the gene expression profile of MSCs. Self-activation of interleukin-1 (IL1) signaling was shown to be upstream of both pro-and anti-inflammatory genes in MSC spheroids, but the molecular pathways that initiate IL1 signaling remain unknown. As bone morphogenic protein (BMP)2 upregulation precedes that of IL1B expression during spheroid formation, we hypothesized that BMP2 signaling triggers IL1 signaling in MSC spheroids. Contrary to expectations, BMP2 signaling decreased expression of IL1B and downstream genes in a SMAD6-dependent manner. Conversely, IL1B signaling enhanced BMP2 expression. Another major difference between two-dimensional (2D) monolayer culture and three-dimensional (3D) spheroid culture is the Young's elasticity modulus, or stiffness, of the materials surrounding the cells, as there is a million-fold difference between a plastic surface for standard 2D culture (GPa) and 3D spheroidal aggregates (0.1 kPa). We tested another hypothesis that soft elasticity-associated mechanosignaling initiates the gene expression change during spheroid formation. Results showed that both BMP2 expression and inflammatory signaling are upregulated in an elasticity-associated signaling-dependent manner in MSCs. Lastly, BMP2 signaling enhanced cell survival and cell spreading of MSC spheroids. In summary, our study suggests that soft elasticity and BMP2 signaling are critical for MSC spheroids.

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Section: Discussionmentioning

confidence: 99%

“…1). Although physiological roles of BMP2 in MSCs have been extensively studied in the context of osteogenic differentiation [20], other roles of BMP2 signaling have not been investigated.…”

Section: Bmp2 Treatment Strongly Reduces Proinflammatory and Anti-infmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Cesarz

Funnell

Guan

et al. 2016

Stem Cells and Development

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“…62 PPARg promotes adipogenesis upon activation while suppressing osteogenesis by downregulating the expression and transactivation ability of Runx2. 33 Although there is no clinical summary of bone cyst formation at the patient level, it has been previously reported in in vivo preclinical studies.…”

Section: James Et Almentioning

confidence: 99%

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

James

LaChaud

Shen

et al. 2016

Tissue Engineering Part B: Reviews

825

769

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Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

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“…3C). At 6 h, ALP-positive preosteo-MSCs to osteoblasts (2) and plays a significant role in osteogenic differentiation of adipose-derived stem cells (52). These reports suggest a specific role for BMP-4 and BMPR-IB in BMP signaling during osteogenic differentiation of MSCs in the suture upon mechanical stimulation.…”

Section: Immunohistochemical Analysis Of Cyr61/ccn1 In the Mouse Cranmentioning

confidence: 82%

<b>Tensile stress stimulates the expression of osteogenic cytokines/growth factors and matricellular proteins in the mouse cranial suture at the site of osteoblast differ</b><b>entiation </b>

et al. 2016

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Mechanical stress promotes osteoblast proliferation and differentiation from mesenchymal stem cells (MSCs). Although numerous growth factors and cytokines are known to regulate this process, information regarding the differentiation of mechanically stimulated osteoblasts from MSCs in in vivo microenvironment is limited. To determine the significant factors involved in this process, we performed a global analysis of differentially expressed genes, in response to tensile stress, in the mouse cranial suture wherein osteoblasts differentiate from MSCs. We found that the gene expression levels of several components involved in bone morphogenetic protein, Wnt, and epithelial growth factor signalings were elevated with tensile stress. Moreover gene expression of some extracellular matrices (ECMs), such as cysteine rich protein 61 (Cyr61)/CCN1 and galectin-9, were upregulated. These ECMs have the ability to modulate the activities of cytokines and are known as matricellular proteins. Cyr61/CCN1 expression was prominently increased in the fibroblastic cells and preosteoblasts in the suture. Thus, for the first time we demonstrated the mechanical stimulation of Cyr61/CCN1 expression in osteogenic cells in an ex vivo system. These results suggest the importance of matricellular proteins along with the cytokine-mediated signaling for the mechanical regulation of MSC proliferation and differentiation into osteoblastic cell lineage in vivo.Mechanical stress controls bone mass by affecting recruitment of osteoprogenitors as well as osteoblast differentiation from mesenchymal stem cells (MSCs) in the bone tissue (7,8). Elucidation of the precise mechanisms involved in the osteoblastogenesis stimulated by mechanical stress, especially the mechanism for osteogenic differentiation of MSCs, will contribute to the progress of regenerative medicine for effective production of bone tissue from MSC sources. Increasing evidence has revealed that the process of mechanical stress-stimulated osteoblastogenesis is controlled by many cytokines/growth factors (9,32,34,36). Especially bone morphogenetic protein (BMP) signaling and Wnt signaling play important roles in the development of osteoblasts from MSCs (5), but the more relevant factors among these or

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The Roles of Bone Morphogenetic Proteins and Their Signaling in the Osteogenesis of Adipose-Derived Stem Cells

Cited by 69 publications

References 97 publications

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

<b>Tensile stress stimulates the expression of osteogenic cytokines/growth factors and matricellular proteins in the mouse cranial suture at the site of osteoblast differ</b><b>entiation </b>

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