Epitope-specific monoclonal antibodies to FSHβ increase bone mass.

Autor:	Ji Y; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; School and Hospital of Stomatology, Wuhan University, Wuhan, 430079 Hubei, China., Liu P; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Yuen T; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Haider S; Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, WC1 1AX London, United Kingdom., He J; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305., Romero R; Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, WC1 1AX London, United Kingdom., Chen H; Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, Stanford University, Stanford, CA 94305., Bloch M; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Kim SM; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Lizneva D; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Reproductive Health Protection, Scientific Center of Family Health and Human Reproduction, 664003 Irkutsk, Russian Federation., Munshi L; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Zhou C; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Lu P; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Iqbal J; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Cheng Z; Molecular Imaging Program at Stanford, Bio-X Program, Department of Radiology, Stanford University, Stanford, CA 94305., New MI; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu mone.zaidi@mssm.edu., Hsueh AJ; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305., Bian Z; School and Hospital of Stomatology, Wuhan University, Wuhan, 430079 Hubei, China., Rosen CJ; Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, ME 04074., Sun L; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Zaidi M; The Mount Sinai Bone Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu mone.zaidi@mssm.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Feb 27; Vol. 115 (9), pp. 2192-2197. Date of Electronic Publication: 2018 Feb 12.
DOI:	10.1073/pnas.1718144115
Abstrakt:	Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that FSH inhibition reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHβ was found not only to rescue bone loss postovariectomy, but also to display marked antiobesity and probeiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance--osteoporosis and obesity--we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHβ. Hf2 has already been shown to reduce body weight and fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on microcomputed tomography. This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild-type mice. We also reconfirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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