Editorial

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J Rheum Dis 2024; 31(3): 133-134

Published online July 1, 2024

© Korean College of Rheumatology

Effect of recombinant human bone morphogenetic protein-2 and osteoprotegerin-Fc in MC3T3-E1 cells: beyond challenges to success

Chang Hoon Lee, M.D., Ph.D.1,2

1Musculoskeletal and Immune Disease Research Institute, School of Medicine, Wonkwang University, 2Division of Rheumatology, Department of Internal Medicine, Wonkwang University Hospital, Iksan, Korea

Correspondence to : Chang Hoon Lee, https://orcid.org/0000-0002-7351-3806
Division of Rheumatology, Department of Internal Medicine, Wonkwang University Hospital, 460 Iksandae-ro, Iksan 54538, Korea. E-mail: lch110@wku.ac.kr

Received: June 24, 2024; Accepted: June 24, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

New therapeutic options of osteoporosis and bone defect are being needed to ensure the best result and stability and decrease the surgical trauma. It is very important that stepwise and combination treatment in osteoporosis to boost osteogenic effects because the limitations of current osteoporosis treatments are clear.

Kim et al. [1] compared the osteogenic effect by recombinant human bone morphogenetic protein-2 (rhBMP-2) and osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc) and revealed the combination promoted the efficacy of the osteoblast differentiation. In particular, the results suggest serial administration of rhBMP-2 and OPG-Fc are essential for best efficacy at an appropriate time in vivo research [1].

Bone morphogenetic proteins promote bone formation by recruiting primitive mesenchymal cells and stimulate osteoblast differentiation [2,3]. However, BMPs can also enhance the catabolic activity of osteoclast [4].

Osteoprotegerin (OPG) enhances osteoclast differentiation, and its effect in osteoblastogenesis remains unclear [5].

OPG may promote bone formation in synergy with bone morphogenetic protein-2 [6] and may have anti-apoptotic effect during osteoblastogenesis [7].

The previous studies were the first to report, through bone histomorphometry, immunohistochemistry, and alkaline phosphatase (ALP) that the expression of BMP-2 is enhanced by OPG, a key factor in maintaining normal bone mass [8-10].

Meanwhile, animal experiments have already been conducted to determine the interaction between rhBMP-2 and OPG. Yao Y et al. [6] revealed that OPG enhanced recruitment of mesenchymal stem cells synergistically with BMP-2 and increased bone formation and healing significantly. Local application of rhBMP-2 promoted significant improvements of osteoblasts, and OPG increased bone density. There was significant synergistic enhancement between BMP-2 and OPG in dog model.

Most recently, in ovariectomized rat model, Eom et al. [11] reported that stepwise administration of OPG encoded minicircles and parathyroid hormone related peptide encoded minicircles enhance bone formation and inhibit bone resorption.

Therefore, it is necessary to examine the results of animal models for combined administration of BMP-2 and OPG based on cell line experiments. In addition, it is necessary to verify changes in collagen type I alpha 1 and osteocalcin, which are representative bone formation promoting indicators of osteoblast differentiation, and their effects on osteoclasts as well as osteoblasts. Furthermore, we recommend confirming that previous researchers thought that the target of OPG would be NF-κB, a major pathway for Receptor activator of nuclear factors κB ligand (RANKL) [12].

This study was supported by Wonkwang University grant in 2023.

No potential conflict of interest relevant to this article was reported.

  1. Kim SH, Choi HJ, Lee SM, Yoon DS, Son CN. Effect of recombinant human bone morphogenetic protein-2 and osteoprotegerin-Fc in MC3T3-E1 cells. J Rheum Dis 2024;31:79-85.
    Pubmed KoreaMed CrossRef
  2. Urist MR. Bone: formation by autoinduction. Science 1965;150:893-9.
    Pubmed CrossRef
  3. Wozney JM. The bone morphogenetic protein family and osteogenesis. Mol Reprod Dev 1992;32:160-7.
    Pubmed CrossRef
  4. Okamoto M, Murai J, Yoshikawa H, Tsumaki N. Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 2006;21:1022-33.
    Pubmed CrossRef
  5. Yu H, de Vos P, Ren Y. Overexpression of osteoprotegerin promotes preosteoblast differentiation to mature osteoblasts. Angle Orthod 2011;81:100-6.
    Pubmed KoreaMed CrossRef
  6. Yao Y, Wang G, Wang Z, Wang C, Zhang H, Liu C. Synergistic enhancement of new bone formation by recombinant human bone morphogenetic protein-2 and osteoprotegerin in trans-sutural distraction osteogenesis: a pilot study in dogs. J Oral Maxillofac Surg 2011;69:e446-55.
    Pubmed CrossRef
  7. Palumbo S, Li WJ. Osteoprotegerin enhances osteogenesis of human mesenchymal stem cells. Tissue Eng Part A 2013;19:2176-87.
    Pubmed CrossRef
  8. Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005;8:751-64.
    Pubmed CrossRef
  9. Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 2005;280:21162-8.
    Pubmed CrossRef
  10. Jackson A, Vayssière B, Garcia T, Newell W, Baron R, Roman-Roman S, et al. Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells. Bone 2005;36:585-98.
    Pubmed CrossRef
  11. Eom YJ, Kim JW, Rim YA, Lim J, Jung SI, Ju JH. Effects of stepwise administration of osteoprotegerin and parathyroid hormone-related peptide DNA vectors on bone formation in ovariectomized rat model. Sci Rep 2024;14:2477.
    Pubmed KoreaMed CrossRef
  12. Boyce BF, Li J, Yao Z, Xing L. Nuclear factor-kappa B regulation of osteoclastogenesis and osteoblastogenesis. Endocrinol Metab (Seoul) 2023;38:504-21.
    Pubmed KoreaMed CrossRef

Article

Editorial

J Rheum Dis 2024; 31(3): 133-134

Published online July 1, 2024 https://doi.org/10.4078/jrd.2024.0079

Copyright © Korean College of Rheumatology.

Effect of recombinant human bone morphogenetic protein-2 and osteoprotegerin-Fc in MC3T3-E1 cells: beyond challenges to success

Chang Hoon Lee, M.D., Ph.D.1,2

1Musculoskeletal and Immune Disease Research Institute, School of Medicine, Wonkwang University, 2Division of Rheumatology, Department of Internal Medicine, Wonkwang University Hospital, Iksan, Korea

Correspondence to:Chang Hoon Lee, https://orcid.org/0000-0002-7351-3806
Division of Rheumatology, Department of Internal Medicine, Wonkwang University Hospital, 460 Iksandae-ro, Iksan 54538, Korea. E-mail: lch110@wku.ac.kr

Received: June 24, 2024; Accepted: June 24, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

New therapeutic options of osteoporosis and bone defect are being needed to ensure the best result and stability and decrease the surgical trauma. It is very important that stepwise and combination treatment in osteoporosis to boost osteogenic effects because the limitations of current osteoporosis treatments are clear.

Kim et al. [1] compared the osteogenic effect by recombinant human bone morphogenetic protein-2 (rhBMP-2) and osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc) and revealed the combination promoted the efficacy of the osteoblast differentiation. In particular, the results suggest serial administration of rhBMP-2 and OPG-Fc are essential for best efficacy at an appropriate time in vivo research [1].

Bone morphogenetic proteins promote bone formation by recruiting primitive mesenchymal cells and stimulate osteoblast differentiation [2,3]. However, BMPs can also enhance the catabolic activity of osteoclast [4].

Osteoprotegerin (OPG) enhances osteoclast differentiation, and its effect in osteoblastogenesis remains unclear [5].

OPG may promote bone formation in synergy with bone morphogenetic protein-2 [6] and may have anti-apoptotic effect during osteoblastogenesis [7].

The previous studies were the first to report, through bone histomorphometry, immunohistochemistry, and alkaline phosphatase (ALP) that the expression of BMP-2 is enhanced by OPG, a key factor in maintaining normal bone mass [8-10].

Meanwhile, animal experiments have already been conducted to determine the interaction between rhBMP-2 and OPG. Yao Y et al. [6] revealed that OPG enhanced recruitment of mesenchymal stem cells synergistically with BMP-2 and increased bone formation and healing significantly. Local application of rhBMP-2 promoted significant improvements of osteoblasts, and OPG increased bone density. There was significant synergistic enhancement between BMP-2 and OPG in dog model.

Most recently, in ovariectomized rat model, Eom et al. [11] reported that stepwise administration of OPG encoded minicircles and parathyroid hormone related peptide encoded minicircles enhance bone formation and inhibit bone resorption.

Therefore, it is necessary to examine the results of animal models for combined administration of BMP-2 and OPG based on cell line experiments. In addition, it is necessary to verify changes in collagen type I alpha 1 and osteocalcin, which are representative bone formation promoting indicators of osteoblast differentiation, and their effects on osteoclasts as well as osteoblasts. Furthermore, we recommend confirming that previous researchers thought that the target of OPG would be NF-κB, a major pathway for Receptor activator of nuclear factors κB ligand (RANKL) [12].

ACKNOWLEDGMENTS

None.

FUNDING

This study was supported by Wonkwang University grant in 2023.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

  1. Kim SH, Choi HJ, Lee SM, Yoon DS, Son CN. Effect of recombinant human bone morphogenetic protein-2 and osteoprotegerin-Fc in MC3T3-E1 cells. J Rheum Dis 2024;31:79-85.
    Pubmed KoreaMed CrossRef
  2. Urist MR. Bone: formation by autoinduction. Science 1965;150:893-9.
    Pubmed CrossRef
  3. Wozney JM. The bone morphogenetic protein family and osteogenesis. Mol Reprod Dev 1992;32:160-7.
    Pubmed CrossRef
  4. Okamoto M, Murai J, Yoshikawa H, Tsumaki N. Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development. J Bone Miner Res 2006;21:1022-33.
    Pubmed CrossRef
  5. Yu H, de Vos P, Ren Y. Overexpression of osteoprotegerin promotes preosteoblast differentiation to mature osteoblasts. Angle Orthod 2011;81:100-6.
    Pubmed KoreaMed CrossRef
  6. Yao Y, Wang G, Wang Z, Wang C, Zhang H, Liu C. Synergistic enhancement of new bone formation by recombinant human bone morphogenetic protein-2 and osteoprotegerin in trans-sutural distraction osteogenesis: a pilot study in dogs. J Oral Maxillofac Surg 2011;69:e446-55.
    Pubmed CrossRef
  7. Palumbo S, Li WJ. Osteoprotegerin enhances osteogenesis of human mesenchymal stem cells. Tissue Eng Part A 2013;19:2176-87.
    Pubmed CrossRef
  8. Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005;8:751-64.
    Pubmed CrossRef
  9. Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, et al. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem 2005;280:21162-8.
    Pubmed CrossRef
  10. Jackson A, Vayssière B, Garcia T, Newell W, Baron R, Roman-Roman S, et al. Gene array analysis of Wnt-regulated genes in C3H10T1/2 cells. Bone 2005;36:585-98.
    Pubmed CrossRef
  11. Eom YJ, Kim JW, Rim YA, Lim J, Jung SI, Ju JH. Effects of stepwise administration of osteoprotegerin and parathyroid hormone-related peptide DNA vectors on bone formation in ovariectomized rat model. Sci Rep 2024;14:2477.
    Pubmed KoreaMed CrossRef
  12. Boyce BF, Li J, Yao Z, Xing L. Nuclear factor-kappa B regulation of osteoclastogenesis and osteoblastogenesis. Endocrinol Metab (Seoul) 2023;38:504-21.
    Pubmed KoreaMed CrossRef
JRD
Jul 01, 2024 Vol.31 No.3, pp. 133~189
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