title: Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss.
abstract: HIV-infected individuals are at an increased risk of osteoporosis despite effective viral suppression. Observations that myostatin null mice have increased bone mass led us to hypothesize that simian immunodeficiency virus (SIV)-associated bone loss may be attenuated by blocking myostatin/TGFβ signaling. In this proof-of-concept study, pair-housed juvenile male rhesus macaques were inoculated with SIVmac239. Four weeks later, animals were treated with vehicle or Fc-conjugated soluble activin receptor IIB (ActR2B·Fc, iv. 10mg∗kg-1∗week-1) - an antagonist of myostatin and related members of TGFβ superfamily. Limb and trunk bone mineral content (BMC) and density (BMD) using dual-energy X-Ray absorptiometry, circulating markers of bone growth and turnover, and serum testosterone levels were measured at baseline and during the 12-week intervention period. The increase in BMC was significantly greater in the ActRIIB.Fc-treated group (+8g) than in the placebo group (-4g) (p<0.05). BMD also increased significantly more in the ActRIIB.Fc-treated macaques (+0.03g/cm2) than in the placebo-treated animals (+0g/cm2) (p<0.005). Serum osteocalcin was about two-fold higher in the ActRIIB.Fc-treated group than in the placebo group (p<0.05), but serum C-terminal telopeptide and testosterone levels did not differ significantly between groups. The expression levels of TNFalpha (p<0.05), GADD45 (p<0.005), and sclerostin (p<0.038) in the bone-marrow were significantly lower in the ActRIIB.Fc-treated group than in the placebo group.
  
  
  
  The administration of ActRIIB.FC in SIV-infected juvenile macaques significantly increases BMC and BMD in association with reduced expression levels of markers of bone marrow inflammation.
authors.affiliation: Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address: wguo2@partners.org.
authors.forename: Wen
authors.initials: W
authors.lastname: Guo
authors.affiliation: Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Karol M
authors.initials: KM
authors.lastname: Pencina
authors.affiliation: Department of Comparative Pathology, New England Primate Research Center, One Pine Hill Drive, PO Box 9102, Southborough, MA 01772-9102, United States.
authors.forename: Karyn
authors.initials: K
authors.lastname: O'Connell
authors.affiliation: Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Monty
authors.initials: M
authors.lastname: Montano
authors.affiliation: Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Liming
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Comparative Pathology, New England Primate Research Center, One Pine Hill Drive, PO Box 9102, Southborough, MA 01772-9102, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Westmoreland
authors.affiliation: Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Glowacki
authors.affiliation: Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States.
authors.forename: Shalender
authors.initials: S
authors.lastname: Bhasin
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001835:Body Weight; D015519:Bone Density; D001853:Bone Marrow / Q000378:metabolism; D001862:Bone Resorption / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control*; D005786:Gene Expression Regulation; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D011961:Receptors, Fc / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000150:complications*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D013739:Testosterone / Q000097:blood
chemical_list: D015415:Biomarkers; D008024:Ligands; D011961:Receptors, Fc; D013739:Testosterone; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
keywords: Bone; Nonhuman primate; SIV; Soluble activin receptor IIB