The soluble form of BMPRIB is a novel therapeutic candidate for treating bone related disorders

Abstract

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the TGF-beta superfamily. Recently, several soluble BMP receptors, such as ActRIIA-Fc, ActRIIB-Fc, and ALK1-Fc, are undergoing clinical trials. Both BMPRIA and BMPRIB are type I BMP receptors, and while BMPRIA-Fc has been reported to have bone-increasing properties, there have been no investigations concerning the biological functions of BMPRIB-Fc. Therefore, comparing the effects of BMPRIA-Fc and BMPRIB-Fc in vivo should be helpful in revealing the differences in biological function between BMPRIA and BMPRIB, and would also aid in the evaluation of BMPRIB-Fc as a therapeutic agent. Here, we produced Tg chimeras in which BMPRIA-Fc and BMPRIB-Fc proteins circulated at high concentrations (36.8–121.4 μg/mL). Both Tg chimeras showed a significant increase of bone volume and strength. Using histological analysis, adenoma of the glandular stomach was observed only in BMPRIA-Fc chimeras suggesting the tumorigenic activity of this protein. Administration of recombinant BMPRIB-Fc protein to normal mice also increased bone volumes. Finally, treatment with BMPRIB-Fc decreased the area of osteolytic regions in a mouse model of breast cancer metastasis. In conclusion, our data suggest that BMPRIB-Fc can be used for the treatment of bone-related disorders with a lower risk than BMPRIA-Fc.

A Synthetic Peptide, CK2.3, Inhibits RANKL-Induced Osteoclastogenesis through BMPRIa and ERK Signaling Pathway

“…BMP receptor type Ib (BMPRIb) was shown to be constantly expressed from Day 0–5 in RANKL-induced osteoclast differentiation and had a weaker affinity (3-fold weaker) for BMP2 than BMPRIa [ 69 , 86 ]. Additionally, soluble forms of BMPRIb show better inhibitory effects on osteoclast formation in vivo than soluble forms of BMPRIa [ 87 ]. Thus, it was speculated that BMPRII bound to BMPRIb on Day 1 to induce the commitment of osteoclast precursors into osteoclasts.…”

BMP9 and BMP10: Two close vascular quiescence partners that stand out

“…On the contrary, BMP10 does not bind to ALK2 and has been proposed to bind to ALK3 and ALK6 52 . However, in another work, it was shown, using surface plasmon resonance (SPR), that BMP10 could bind ALK6 but not ALK3 53 . Therefore, a better characterization of the binding and activation of ALK3 or ALK6 by BMP10 at both the biochemical and the cellular level is needed.…”

“…52 However, in another work, it was shown, using surface plasmon resonance (SPR), that BMP10 could bind ALK6 but not ALK3. 53 Therefore, a better characterization of the binding and activation of ALK3 or ALK6 by BMP10 at both the biochemical and the cellular level is needed. Both BMP10 and BMP10-pd can activate cells expressing ALK1 (mostly endothelial cells) but the C2C12 muscle cell line, which does not express ALK1, is activated by mature BMP10 but not by BMP10-pd 54,55 supporting that BMP10 prodomain could differentially control BMP10 activity depending on the type I receptor.…”

Anabolic Strategies to Augment Bone Fracture Healing

“…As such, ligand sinks (receptor extracellular domain-Fc) have been formulated from the major receptors of the TGFβ superfamily for the potential treatment of bone disease. Fc fusion proteins of type I BMP receptors (BMPRIA and BMPRIB) [ 72 ] and type II receptors (ActRIIA, ActRIIB) have been shown to stimulate bone mass accrual. Indeed, a soluble ActRIIA molecule was able to promote bone formation during fracture repair; however, the bone was of lesser quality compared to controls, which may be due to the negative effect of this molecule on osteoclast formation [ 73 ].…”