title: 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.
authors.affiliation: Nephrology Research Labs., Nephrology R&D Unit, R&D division, Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo, 194-8533, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Yamawaki
authors.affiliation: Nephrology Research Labs., Nephrology R&D Unit, R&D division, Kyowa Hakko Kirin Co., Ltd., 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Tokyo Research Park, Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo, 194-8533, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Okada
authors.affiliation: R&D division, Oncology R&D Unit, Oncology Research Labs., Kyowa Hakko Kirin Co., Ltd., 1188, Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Oshima
authors.affiliation: Production division, Bio Process Research and Development Labs., Kyowa Hakko Kirin Co., Ltd., 100-1 Hagiwara-machi, Takasaki-shi, Gunma, 370-0013, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kakitani
authors.affiliation: R&D division, Research Functions Unit, Innovative Technology Labs., Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo, 194-8533, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Tomizuka
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000097:blood / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D018786:Bone Substitutes; D004195:Disease Models, Animal; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D010014:Osteolysis / Q000188:drug therapy; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D055114:X-Ray Microtomography
chemical_list: D018786:Bone Substitutes; D008024:Ligands; D011994:Recombinant Proteins; D052005:Bone Morphogenetic Protein Receptors, Type I