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Cited by 348TGF-β signaling in diseasesBone Metabolism and DiseasesDevelopmental Biology and Gene Regulation

The DOI matches its Crossref record; 310 of the 312 references it cites were found in a registry or an index.

Bone Morphogenetic Protein-2 in Development and Bone Homeostasis

Open access
Halloran, Daniel, Durbano, Hilary W., Nohe, Anja·2020·Journal of Developmental Biology
DOI 10.3390/jdb8030019PMC PMC7557435
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Abstract

Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the Transforming Growth Factor-Beta (TGF-β) superfamily. These proteins are essential to many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis. Specifically, within the BMP family, Bone Morphogenetic Protein-2 (BMP-2) was the first BMP to be characterized and has been well-studied. BMP-2 has important roles during embryonic development, as well as bone remodeling and homeostasis in adulthood. Some of its specific functions include digit formation and activating osteogenic genes, such as Runt-Related Transcription Factor 2 (RUNX2). Because of its diverse functions and osteogenic potential, the Food and Drug Administration (FDA) approved usage of recombinant human BMP-2 (rhBMP-2) during spinal fusion surgery, tibial shaft repair, and maxillary sinus reconstructive surgery. However, shortly after initial injections of rhBMP-2, several adverse complications were reported, and alternative therapeutics have been developed to limit these side-effects. As the clinical application of BMP-2 is largely implicated in bone, we focus primarily on its role in bone. However, we also describe briefly the role of BMP-2 in development. We then focus on the structure of BMP-2, its activation and regulation signaling pathways, BMP-2 clinical applications, and limitations of using BMP-2 as a therapeutic. Further, this review explores other potential treatments that may be useful in treating bone disorders.

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Crossref · 10.3390/jdb8030019

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Figures

Figure 1 The bone microenvironment. Healthy bone function and renewal is controlled by the activity of osteoblasts and osteoclasts. Osteoblasts derive from MSCs, which commit to the osteoblast lineage after exposure to BMP-2. BMP-2 is secreted into the bone matrix or bloodstream by pre-existing osteoblasts, osteocytes, and endothelial cells, where it can bind to bone morphogenetic protein receptors (BMPRs) on MSCs. After MSCs differentiate into osteoblasts, these cells secrete the organic matrix of the bone. Some eventually become embedded within the bone as osteocytes, which provide further structure. HSCs differentiate into osteoclasts after being stimulated with factors, such as RANK-L and NF-kB. The osteoclasts are multinucleated and resorb the bone matrix, releasing contents (i.e., BMP-2 and calcium) to be recycled throughout the body.
Figure 1 The bone microenvironment. Healthy bone function and renewal is controlled by the activity of osteoblasts and osteoclasts. Osteoblasts derive from MSCs, which commit to the osteoblast lineage after exposure to BMP-2. BMP-2 is secreted into the bone matrix or bloodstream by pre-existing osteoblasts, osteocytes, and endothelial cells, where it can bind to bone morphogenetic protein receptors (BMPRs) on MSCs. After MSCs differentiate into osteoblasts, these cells secrete the organic matrix of the bone. Some eventually become embedded within the bone as osteocytes, which provide further structure. HSCs differentiate into osteoclasts after being stimulated with factors, such as RANK-L and NF-kB. The osteoclasts are multinucleated and resorb the bone matrix, releasing contents (i.e., BMP-2 and calcium) to be recycled throughout the body.CC BY · PubMed Central
Figure 2 Differentiation of MSCs to osteoblasts driven by BMP-2, along with the other listed factors. MSCs are located in bone marrow and differentiate into pre-osteoblasts when exposed to RUNX2 and BMP-2. The pre-osteoblasts differentiate into inactive osteoblasts in the presence of RUNX2, BMP-2, and Osx. Inactive osteoblasts become active osteoblasts in bone microenvironments that require rebuilding, and BMP-2 can also assist in this process. Active osteoblasts can then become embedded in bone and function as osteocytes.
Figure 2 Differentiation of MSCs to osteoblasts driven by BMP-2, along with the other listed factors. MSCs are located in bone marrow and differentiate into pre-osteoblasts when exposed to RUNX2 and BMP-2. The pre-osteoblasts differentiate into inactive osteoblasts in the presence of RUNX2, BMP-2, and Osx. Inactive osteoblasts become active osteoblasts in bone microenvironments that require rebuilding, and BMP-2 can also assist in this process. Active osteoblasts can then become embedded in bone and function as osteocytes.CC BY · PubMed Central
Figure 3 Bone Morphogenic Protein 2 (BMP-2) activation of signaling pathways. Once BMP-2 binds to the BMPRs located in lipid rafts, caveolae, and clathrin coated pits (CCPs), constitutively active BMPRII phosphorylates BMPRIa. This leads to downstream activation of the Smad pathway or the non-Smad pathways. In non-Smad signaling, the extracellular signal-related kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and the transforming growth factor-β-activated kinase 1/binding protein 1 (TAB1/TAK1) pathways are activated. All of these pathways, except for NF-kB, lead to an increased differentiation of MSCs and osteoprogenitors into osteoblasts.
Figure 3 Bone Morphogenic Protein 2 (BMP-2) activation of signaling pathways. Once BMP-2 binds to the BMPRs located in lipid rafts, caveolae, and clathrin coated pits (CCPs), constitutively active BMPRII phosphorylates BMPRIa. This leads to downstream activation of the Smad pathway or the non-Smad pathways. In non-Smad signaling, the extracellular signal-related kinase (ERK), phosphatidylinositol 3-kinase (PI3K), and the transforming growth factor-β-activated kinase 1/binding protein 1 (TAB1/TAK1) pathways are activated. All of these pathways, except for NF-kB, lead to an increased differentiation of MSCs and osteoprogenitors into osteoblasts.CC BY · PubMed Central
Figure 4 Activation and inactivation of Smad signaling without exogenous BMP-2. (A) CK2.3 is endocytosed into cells via caveolae, and then binds to CK2 to prevent its association with BMPRIa. This results in activation of Smad and non-Smad signaling pathways (such as ERK), leading to osteogenesis. (B) Alternatively, BMPRIa inhibitors, such as Dorsomorphin (DMH1), specifically bind to the receptor and inhibit Smad-signaling to limit arterial calcification by limiting Ca2+ accumulation. Further, DMH1 has been implicated in slowing tumor progression and metastasis.
Figure 4 Activation and inactivation of Smad signaling without exogenous BMP-2. (A) CK2.3 is endocytosed into cells via caveolae, and then binds to CK2 to prevent its association with BMPRIa. This results in activation of Smad and non-Smad signaling pathways (such as ERK), leading to osteogenesis. (B) Alternatively, BMPRIa inhibitors, such as Dorsomorphin (DMH1), specifically bind to the receptor and inhibit Smad-signaling to limit arterial calcification by limiting Ca2+ accumulation. Further, DMH1 has been implicated in slowing tumor progression and metastasis.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Steele, D.G., and Bramblett, C.A. (1988). The Anatomy and Biology of the Human Skeleton, Texas A&M University Press.
  2. (2020, April 23). The Basics of Bone in Health and Disease, Available online: https://www.ncbi.nlm.nih.gov/books/NBK45504/.

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Metadata

Authors
Halloran, D., Durbano, H. W., & Nohe, A.
Affiliations
University of Delaware (US)
Corresponding author
Nohe, Anja
ORCID
Venue
Journal of Developmental Biology
Publisher
MDPI AG
Published
2020-09-13
Volume
8
Issue
3
Pages
19
ISSN
2221-3759 (ISSN-L)
DOI
10.3390/jdb8030019
PMC
PMC7557435
OpenAlex
W3085579791
Cited by
348
References
312
Citations by year
2026: 57 · 2025: 86 · 2024: 79 · 2023: 42 · 2022: 55 · 2021: 27 · 2020: 1
FWCI
2.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
BMP-2, BMP signaling, TGF-beta superfamily, bone homeostasis, bone remodeling, bone formation, embryonic development, digit formation, Runx2, recombinant human BMP-2, bone graft substitutes, spinal fusion, maxillary sinus reconstruction, bone disease

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