INTRODUCTION:

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily.¹Many BMPs are produced in bone and show osteogenic activity, suggesting that they may be determinants of bone mass. BMP3 was originally purified from bone as osteogenin, which induces osteogenic differentiation.²Bone morphogenic protein (BMP 3) is the most abundant BMP in bone, accounting for more than 65% of the total BMP stored in the bone matrix. Most of the physiological and pathological processes occurring in the body like fracture healing, mechanical loading of the skeleton, development, and osteoporosis are regulated by BMP 3.^3,4,5

Recombinant BMP3 (rhBMP3) has no biological activity, however, leaving its role in skeletal growth unclear.⁶BMP3 is an antagonist of osteogenic BMPs and these effects appear to be mediated through activin receptors. Finally, Bmp3 have twice as much trabecular bone as wild-type littermates, indicating that BMP3, the most abundant BMP in adult bone, is a negative determinant of bone density.^7,8

Osteoblast differentiation is inhibited by BMP 3 and it acts as a negative regulator of bone density. Bone morphogenic protein 3 interferes with osteogenic BMPs by binding to a shared receptor while having no inherent signaling function.^9,10This article reviews the various functions of bone morphogenic protein 3 and its clinical applications.

FUNCTIONS:

Negatively regulates bone density. It antagonizes the ability of certain osteogenic BMPs to induce osteoprogenitor differentiation and ossification.

Molecular function of BMP 3

· BMP receptor binding

· cytokine activity

· receptor binding¹¹

· transforms growth factor by beta receptor binding

Biological process of BMP 3 (Fig 1)

· BMP signalling pathway¹²

· cartilage development¹³

· cell-cell signalling

· cell development

· Bone growth¹⁴

· osteoblast differentiation

· positive regulation of pathway-restricted SMAD protein phosphorylation¹⁴

· regulation of apoptotic process

· regulation of MAPK cascade

· skeletal system development¹⁵

· SMAD protein signal transduction¹⁶

Fig 1. BMP Signalling pathway and regulation of miRNA levels

Function of BMP 3 on receptor binding:

Activin is antagonized by BMP-3 and BMP signalling upstream the receptor activation. BMP and activin signaling are tightly regulated during embryonic development by potent extracellular antagonists that bind directly to these ligands, preventing them from interacting with their receptors. Extracellular antagonists can also inhibit signalling in an indirect manner, where the ligand up regulates antagonist expression creating a negative feedback loop. BMP-3 itself was an extracellular ligand antagonist because it is unable to show direct binding of BMP-3 to other BMPs or activin.^17,18,19Investigation on BMP shows that whether BMP-3 could block the effects of constitutively activated type I activin or BMP receptors in the animal cap assay by looking for induction of mesodermal marker genes by these receptors.²⁰If BMP-3 acts intracellularly by interfering with receptor activation, it should observe a down regulation of mesodermal marker expression. Conversely, if BMP-3 inhibits signalling upstream of the receptor, marker gene expression should be unaffected²¹.

It was found that BMP-3 was unable to block CA-ALK3 or CA-ALK4 from inducing the expression of Xbra or muscle actin. The data indicate that BMP-3 acts upstream of receptor activation before R-Smad phosphorylation by type I receptor.^22,23

Injected 4-cell embryos with BMP-3, BMP-4 or activin mRNA and examined R-Smad phosphorylation in isolated animal cap explants at stage 10.5. A Western blot analysis showed strong phosphorylation of Smad1, 5, 8 by BMP-4 and phosphorylation of Smad2 by activin. Surprisingly, it was detected phosphorylation of any R-Smads by BMP-3 alone. When co-injected BMP-3 together with BMP-4 or activin, found that BMP-3 decreased the level of phosphorylation of Smad1, 5, 8 and strongly reduced the phosphorylation level of Smad2. Based on these findings the results confirm that BMP-3 antagonizes signaling by activin and BMP and identifies BMP-3 as an inhibitor of signal transmission at the level of ligand binding to receptor.^{24, 25}

Role of BMP 3 in bone formation:

BMPs are emerging as key modulators of the various growth factors involved in the healing response after a fracture and induces endochondral bone formation in vivo. The locations of the BMP genes found to overlap with the loci for several disorders of cartilage and bone formation. Diseases associated with BMP 3 include Dentine Erosion and Chromosome 4Q21 Deletion Syndrome. It antagonises the ability of certain osteogenic BMPs to induce osteoprogenitor differentiation and ossificationand negatively regulates bone density^{26, 27}.

The effect of BMP 3 on articular cartilage repair:

BMP 3 inhibits the repair of partial-thickness cartilage defects by inducing the degradation of the extracellular matrix and interfering with the survival of chondrocytes surrounding the defect. Meanwhile BMP 3 also suppresses the repair of full-thickness cartilage defects by destroying the subchondral bone. Studies revealed that BMP 3 increased the proliferation of chondrocytes and BMSCs.^28,29,30However, it inhibits the synthesis or fastens the degradation of type II collagen in them³¹. BMP 3 plays important roles in bone formation and is modulated by mechanical loading.³²BMP 3 is strongly expressed in the developing perichondrium and improved cartilage cell proliferation by modulating BMP signaling through the type II receptor activin receptor type 2b (Acvr2b), which further affected bone formation. ³³Moreover, the expression of BMP 3 in the special layer of articular cartilage is correlated with mechanical loading. In addition, BMP 3 may also play important roles in articular cartilage repair³⁴.

It was found that exogenous BMP 3 inhibits partial-thickness articular cartilage repair through regulating chondrocytes, which is associated with the BMP signaling pathway by regulating the expression of BMP 2 and BMP 4.³⁵BMP 3 impaired the poor spontaneous repair ability of articular cartilage by inducing the degeneration of ECM and inhibiting the survival of chondrocytes. As BMP 3 down-regulated the expression of COL2A1 and COL1A2 and up-regulated the expression of MMP13 for chondrocytes in vitro, it will lead to the matrix degradation of cultured chondrocytes and cartilage. Although it increases the proliferation of chondrocytes in vitro, the destroyed ECM can inhibit the survival of chondrocytes.^36,37

For bone marrow stromal cells (BMSCs), BMP 3 up-regulates the expression of COL1A2 and COL2A1 to improve the synthesis of ECM, meanwhile it also up-regulates the expression of BMP 4 to increase BMP signalling (Fig 2).

Fig 2. Function of BMP 3 between chrondrocytes and BMSCs

BMP has also recently been shown to promote the proliferation of the mesenchymal stem cells and may play a role in adipogenesis.^38,39

CONCLUSION:

Bone morphogenic protein 3 plays an essential role as a modulator of osteogenic BMPs. Although therapies to accelerate bone healing have used BMP-2 and BMP-7, inhibition of BMP-3 would have the same effect, perhaps at a lower cost. Bone morphogenic protein 3 provides a novel therapeutic intervention point for the treatment of diseases from osteopenia to fracture nonunion.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 26.11.2017 Modified on 14.12.2017

Research J. Pharm. and Tech. 2018; 11(3): 1251-1254.

DOI: 10.5958/0974-360X.2018.00233.0