title: Type 1 interferons suppress accelerated osteoclastogenesis and prevent loss of bone mass during systemic inflammatory responses to Pneumocystis lung infection.
abstract: HIV infection causes loss of CD4(+) T cells and type 1 interferon (IFN)-producing and IFN-responsive dendritic cells, resulting in immunodeficiencies and susceptibility to opportunistic infections, such as Pneumocystis. Osteoporosis and bone marrow failure are additional unexplained complications in HIV-positive patients and patients with AIDS, respectively. We recently demonstrated that mice that lack lymphocytes and IFN a/b receptor (IFrag(-/-)) develop bone marrow failure after Pneumocystis lung infection, whereas lymphocyte-deficient, IFN α/β receptor-competent mice (RAG(-/-)) had normal hematopoiesis. Interestingly, infected IFrag(-/-) mice also exhibited bone fragility, suggesting loss of bone mass. We quantified bone changes and evaluated the potential connection between progressing bone fragility and bone marrow failure after Pneumocystis lung infection in IFrag(-/-) mice. We found that Pneumocystis infection accelerated osteoclastogenesis as bone marrow failure progressed. This finding was consistent with induction of osteoclastogenic factors, including receptor-activated nuclear factor-κB ligand and the proapoptotic factor tumor necrosis factor-related apoptosis-inducing ligand, in conjunction with their shared decoy receptor osteoprotegerin, in the bone marrow of infected IFrag(-/-) mice. Deregulation of this axis has also been observed in HIV-positive individuals. Biphosphonate treatment of IFrag(-/-) mice prevented bone loss and protected loss of hematopoietic precursor cells that maintained activity in vitro but did not prevent loss of mature neutrophils. Together, these data show that bone loss and bone marrow failure are partially linked, which suggests that the deregulation of the receptor-activated nuclear factor-κB ligand/osteoprotegerin/tumor necrosis factor-related apoptosis-inducing ligand axis may connect the two phenotypes in our model.
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Wilkison
authors.forename: Katherine
authors.initials: K
authors.lastname: Gauss
authors.forename: Yanchao
authors.initials: Y
authors.lastname: Ran
authors.forename: Steve
authors.initials: S
authors.lastname: Searles
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.forename: Nicole
authors.initials: N
authors.lastname: Meissner
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004164:Diphosphonates / Q000627:therapeutic use; D018450:Disease Progression; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D006457:Hemoglobinuria, Paroxysmal / Q000382:microbiology / Q000503:physiopathology / Q000517:prevention & control; D007370:Interferon Type I / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology*; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000382:microbiology* / Q000503:physiopathology / Q000517:prevention & control; D053244:Osteoprotegerin / Q000378:metabolism; D011020:Pneumonia, Pneumocystis / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D053245:RANK Ligand / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000382:microbiology* / Q000503:physiopathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D055114:X-Ray Microtomography
chemical_list: D050071:Bone Density Conservation Agents; D016207:Cytokines; D004164:Diphosphonates; D007370:Interferon Type I; D053244:Osteoprotegerin; D053245:RANK Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C506031:Tnfrsf11b protein, mouse; C505654:Tnfsf10 protein, mouse; C505689:Tnfsf11 protein, mouse