title: Proteoglycan 4, a novel immunomodulatory factor, regulates parathyroid hormone actions on hematopoietic cells.
abstract: Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4(-/-) mutant and Prg4(+/+) wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220(+) (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin(-)Sca-1(+)c-Kit(+) (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTH-stimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.
authors.affiliation: Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Novince
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Koh
authors.forename: Megan N
authors.initials: MN
authors.lastname: Michalski
authors.forename: Julie T
authors.initials: JT
authors.lastname: Marchesan
authors.forename: Jason
authors.initials: J
authors.lastname: Wang
authors.forename: Younghun
authors.initials: Y
authors.lastname: Jung
authors.forename: Janice E
authors.initials: JE
authors.lastname: Berry
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Eber
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Rosol
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
authors.forename: Laurie K
authors.initials: LK
authors.lastname: McCauley
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013926:Thrombopoietin / Q000378:metabolism; D000099158:Proteoglycan 4
chemical_list: D054377:Chemokine CXCL12; D015850:Interleukin-6; D010281:Parathyroid Hormone; D011509:Proteoglycans; D012333:RNA, Messenger; D013926:Thrombopoietin; C515256:Cxcl12 protein, mouse; C498837:Prg4 protein, mouse; D000099158:Proteoglycan 4