Editors' ChoiceBone Biology

Bone-Building T Cells

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Science Signaling  08 Sep 2009:
Vol. 2, Issue 87, pp. ec295
DOI: 10.1126/scisignal.287ec295

Bone mass is decreased by continuous exposure to parathyroid hormone (PTH) but increased by intermittent exposure. Daily injections of PTH to mimic intermittent PTH (iPTH) are used to treat osteoporosis. PTH activates Wnt signaling pathways that require the co-receptors LRP5 and LRP6 (low-density lipoprotein receptor–related protein). Although loss-of-function mutations in LRP5 decrease bone mass in humans and mice, they do not abolish the ability of PTH to promote bone formation in mice. Complementing previous work that identified the role of T cells in bone cell responses to continuous PTH, Terauchi et al. assessed the role of T cells in response to iPTH. Wild-type mice exhibited a greater anabolic response to iPTH compared with mice lacking αβ T cells (TCRβ–/–), as assessed by several measures of bone accretion, including bone mineral density (BMD), trabecular bone volume (BV/TV), bone strength, and serum concentrations of osteocalcin (a marker of bone differentiation). These decreased responses were rescued in TCRβ–/– mice by adoptive transfer of wild-type T cells prior to iPTH. Anabolic responses to iPTH were mediated primarily by CD8+ cells, because adoptive transfer of CD8+ cells, but not CD4+ T cells, into TCRβ–/– mice restored responses to iPTH. Stromal cell commitment to the osteoblastic lineage, as measured by formation of alkaline phosphatase–positive colony-forming unit fibroblasts, was increased by iPTH treatment of bone marrow from wild-type mice, but not that from TCRβ–/– mice. Pre-osteoblasts from iPTH-treated wild-type mouse bone marrow exhibited greater proliferation, decreased apoptosis, and increased expression of genes indicative of osteoblastic differentiation, as well as those activated by Wnt signaling, compared with those from iPTH-treated TCRβ–/– mouse bone marrow. iPTH treatment of CD8+ T cells increased the abundance of the mRNA and protein for the Wnt ligand Wnt10b. Adoptive transfer of T cells from Wnt10b–/– mice failed to restore the response to iPTH in TCRβ–/– mice, as assessed by BV/TV measurements and osteocalcin concentrations. Thus, the anabolic effects of iPTH on osteoblasts appear to be mediated in part by the release of Wnt10b by CD8+ T cells.

M. Terauchi, J.-Y. Li, B. Bedi, K.-H. Baek, H. Tawfeek, S. Galley, L. Gilbert, M. S. Nanes, M. Zayzafoon, R. Guldberg, D. L. Lamar, M. A. Singer, T. F. Lane, H. M. Kronenberg, M. N. Weitzmann, R. Pacifici, T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metabol. 10, 229–240 (2009). [PubMed]

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