Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells

Luu, Hue H.; Song, Wen Xin; Luο, Xingguang; Manning, David W.; Luo, Jinyong; Deng, Zhong Liang; Sharff, Katie A.; Montag, Anthony; Haydon, Rex C.; He, Tong Chuan

doi:10.1002/jor.20359

Cited by 483 publications

(561 citation statements)

References 48 publications

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“…9,10,40 The cell cultures used in our study constitute a mixed population of different cell types and stages of differentiation to mimic in vivo cell populations. Nevertheless, bone formation is a complex process that may occur through endochondral or intramembraneous ossification preceded by bone resorption.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have addressed the combined effects of BMPs on osteogenesis, mainly focusing on BMP-2 and BMP-7. 9,10 We showed that BMP-2, BMP-5, and BMP-6 alone have distinct and diverse effects on osteoclasts and osteoblasts in vitro. 8 The aim of the present study was to investigate the effects of the simultaneous use of BMP-2, BMP-5, and BMP-6 on osteoblast and osteoclast generation to test the hypothesis that BMPs in combination exert synergistic effects on processes of bone regeneration.…”

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confidence: 99%

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Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro

Wutzl

Rauner

Seemann

et al. 2010

Journal Orthopaedic Research

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Bone regeneration is required for fracture healing. Various procedures have been used to promote osteogenesis with bone morphogenetic proteins (BMPs). We assessed the effects of BMP-2, BMP-5, and BMP-6 in isolated and combined use on the generation of osteoblasts and osteoclasts by comparing the osteoclastic potency of each on osteoclasts of primary murine bone marrow cells. Subsequently, cells were stained for tartrate-resistant acid phosphatase, and real time PCR analysis of receptor activator of NK B ligand and osteoprotegerin was conducted. The same combination of BMPs was used to assess their potential to enhance osteoblasts, employing a mineralization assay and real-time PCR analysis of collagen type-1, runx2, and osterix. While BMP-2 alone and the combination of BMP-2 and BMP-5 significantly enhanced osteoclastogenesis, BMP-2, BMP-5, and BMP-6 in combination did not have additional effects. However, the combined use of BMP-2, BMP-5, and BMP-6 had an additive effect on matrix mineralization and osterix expression in osteoblasts. Our study shows that the combination of BMP-2, BMP-5, and BMP-6 stimulates osteoblasts but not osteoclastogenesis. Keywords: BMP-2; BMP-5; BMP-6; osteoclast; osteoblast Bone undergoes continuous remodeling and is one of the few organs that retains its potential for regeneration in adult life. 1,2 Bone regeneration results from resorption and formation, subject to the generation and activity of osteoclasts and osteoblasts. This balance is regulated by systemic hormones and local factors such as growth factors, cytokines, and prostaglandins.Bone morphogenetic proteins (BMPs) have become interesting therapeutic targets to promote bone regeneration. In vitro studies showed that BMPs regulate cell proliferation, differentiation, and apoptosis in a variety of cell types. BMPs induce the differentiation of mesenchymal cells into osteogenic cells and enhance the function of mature osteoblasts, 3−6 establishing an osteogenic hierarchical model in which BMP-2 and BMP-6 have the greatest effects in inducing osteoblast differentiation. 7−10 In addition, some BMPs stimulate osteoclast formation. 8,11 Hence, BMPs act on osteoclastic bone resorption and cartilage and bone formation, thereby spanning all process of bone remodeling. 12 Recombinant forms of BMPs, especially BMP-2 and BMP-7, induce bone formation in vivo and both were tested in clinical trials. 13−22 The data suggest that BMP-induced bone formation is at least equivalent to autogenous bone grafting when used in alveolar bone grafting, spinal fusion, and tibia non-union.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro

Wutzl

Rauner

Seemann

et al. 2010

Journal Orthopaedic Research

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“…2,3 Mesenchymal stem cells (MSCs) are adherent bone marrow stromal cells that can differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. [17][18][19][20][21] Osteoblastic differentiation of MSCs is an essential process of bone formation, [17][18][19][20] and is tightly regulated. 20,21 BMPs play an important role in osteoblast differentiation.…”

mentioning

confidence: 99%

“…[17][18][19][20][21] Osteoblastic differentiation of MSCs is an essential process of bone formation, [17][18][19][20] and is tightly regulated. 20,21 BMPs play an important role in osteoblast differentiation. 20,[22][23][24] We have analyzed the osteogenic potential of 14 human BMPs and found that BMP-2, 6, 9 are the most potent inducers of osteogenic differentiation both in vitro and in vivo.…”

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confidence: 99%

Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects

Luο

Chen

Song

et al. 2008

Laboratory Investigation

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Osteosarcoma (OS) is the most common primary malignancy of bone. Here, we investigated a possible role of defective osteoblast differentiation in OS tumorigenesis. We found that basal levels of the early osteogenic marker alkaline phosphatase (ALP) activity were low in OS lines. Osteogenic regulators Runx2 and OSX, and the late marker osteopontin (OPN) expressed at low levels in most OS lines, indicating that most OS cells fail to undergo terminal differentiation. Furthermore, OS cells were refractory to osteogenic BMP-induced increases in ALP activity. Osteogenic BMPs were shown to upregulate early target genes, but not late osteogenic markers OPN and osteocalcin (OC). Furthermore, osteogenic BMPs failed to induce bone formation from human OS cells, rather effectively promoted OS tumor growth in an orthotopic OS model. Exogenous expression of early target genes enhanced BMP-stimulated OS tumor growth, whereas osteogenic BMP-promoted OS tumor growth was inhibited by exogenous Runx2 expression. These results suggest that alterations in osteoprogenitors may disrupt osteogenic differentiation pathway. Thus, identifying potential differentiation defects in OS tumors would allow us to reconstruct the tumorigenic events in osteoprogenitors and to develop rational differentiation therapies for clinical OS management.

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“…(1,2) Several BMPs play an especially critical role in differentiation of precursor cells to induce bone formation. (3) Of the BMPs, BMP-2 is the most well studied inducer of osteoblast differentiation and bone formation. (4) BMP-2 is approved for clinical application to induce new bone formation in spine and severe fracture patients, but the amount of recombinant protein required makes its use prohibitively expensive.…”

Section: Introductionmentioning

confidence: 99%

Activation of c-Jun NH2-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor

Liu

Viggeswarapu

et al. 2010

Journal of Bone and Mineral Research

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Bone morphogenetic protein 2 (BMP-2) plays a critical role in the differentiation of precursor cells and has been approved for clinical application to induce new bone formation. To date, unexpectedly high doses of recombinant BMP-2 have been required to induce bone healing in humans. Thus, enhancing cellular responsiveness to BMP-2 potentially has critically important clinical implications. BMP responsiveness may be modulated in part by cross-talk with other signaling pathways, including mitogen-activated protein kinases (MAPKs). c-Jun NH 2 -terminal kinase (JNK) is a MAPK that has been reported to be required for late-stage differentiation of preosteoblasts and BMP-2-induced differentiation of preosteoblasts and pleuripotent cells. In this study we determined that MC3T3-E1-clone 24 cells (MC-24) can be induced by BMP-2 to differentiate into mineralizing osteoblast cultures. Using this inducible system, we employed both JNK loss-of-function and gain-of-function reagents to make three key observations: (1) JNK is required for phosphorylation of Smad1 by BMP-2 and subsequent activation of Smad1 signaling and osteoblast differentiation, (2) JNK1, but not JNK2, is required for BMP-2-induced formation of mineralized nodules, and (3) JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1, both observations that would increase responsiveness to BMP-2. Understanding this and other pathways that lead to increased cellular responsiveness to BMPs could greatly aid more cost-effective and safe clinical delivery of these important molecules. ß

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Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells

Cited by 483 publications

References 48 publications

Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro

Bone morphogenetic proteins 2, 5, and 6 in combination stimulate osteoblasts but not osteoclasts in vitro

Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects

Activation of c-Jun NH2-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor

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