Bone Morphogenetic Protein-2 in Development and Bone Homeostasis

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.

Keywords: BMP-2; CK2; CK2.3; Smad1/5/8; development; osteoblasts; osteoclasts; osteoporosis.

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 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 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 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.