Differential regulation of osteoblast activity by Th cell subsets mediated by parathyroid hormone and IFN-gamma.
Bone loss is a typical pathological feature of chronic inflammatory bone diseases including rheumatoid arthritis, in which CD4 effector T cells play critical roles. We found that activated mouse Th2 and not Th1 cells produced the parathyroid hormone (PTH). Unlike in the parathyroid cells, PTH expression in Th2 cells was not regulated by the fluctuation of calcium level, but rather it required the full activation of the T cells. Although PTH was expressed in immature Th2 cells, and its receptor was transiently expressed during Th1 and Th2 cell differentiation, PTH did not significantly affect the outcome of the differentiation. In primary osteoblasts cultured in Th2 cell condition medium, the alkaline phosphatase (ALP) activity was maintained at a basal level. However, antagonizing PTH in the condition medium resulted in a significant reduction of the ALP activity. These results demonstrated an important role of the Th2 cell-derived PTH in maintaining the bone-forming activity of the osteoblasts under inflammatory conditions. In osteoblasts cultured in the Th1 cell condition medium, the ALP activity was significantly suppressed. Neutralizing IFN-gamma alleviated the suppression. Conversely, treatment of osteoblasts with IFN-gamma suppressed the ALP activity. Unlike ALP, expression of the major bone matrix proteins by the osteoblasts was only minimally affected by either Th1 or Th2 cytokine environment. In addition, the Th2 cytokine environment also regulated to expression of receptor activator of NF-kappaB ligand and osteoprotegerin through both PTH-dependent and -independent mechanisms. Our study therefore identified new regulatory events in bone remodeling under inflammatory conditions.
Young
Nathan
N
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Mikhalkevich
Natallia
N
Yan
Ying
Y
Chen
Di
D
Zheng
Wei-ping
WP
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001857:Bone Matrix; D016723:Bone Remodeling; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D010006:Osteoblasts / Q000378:metabolism*; D019899:Paracrine Communication; D010281:Parathyroid Hormone / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000502:physiology*
D017077:Culture Media, Conditioned; D010281:Parathyroid Hormone; D007371:Interferon-gamma; D000469:Alkaline Phosphatase