In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 12 ( 2012-03-20)
Abstract:
Our findings provide previously undescribed insight into the signaling integration between cells of the immune system (T cells) and bone cells, and the impact of such cellular interaction on bone homeostasis. Understanding the PPR signaling in T cells may therefore yield unique therapeutic strategies for increasing the activity of agents used to treat osteoporosis. Next, we addressed the main question of the study: whether iPTH increases bone volume by directly activating the PPR in T cells. We found that the capacity of iPTH to increase trabecular bone volume was decreased but not completely abolished in young PPR T cells−/− mice. By contrast, the anabolic activity of iPTH was completely blocked in mature PPR T cells−/− mice. These findings suggest that the contribution of T cells to the activity of iPTH increases with age. Analysis of histomorphometric and biochemical indices of bone turnover and cellular studies revealed that PPR silencing in T cells blunts iPTH's normal stimulation of osteoblastogenesis and bone turnover. In summary, our data demonstrate that T cells are direct targets of PTH and play a pivotal role in the osteoblastogenic response to iPTH ( Fig. P1 ). To determine the relevance of Wnt10b for the anabolic activity of iPTH, we injected WT and Wnt10b −/− mice with vehicle or iPTH daily for 4 wk. In WT mice, iPTH treatment significantly increased trabecular bone volume. By contrast, iPTH had no anabolic effects in Wnt10b −/− mice, thus confirming that Wnt10b is required for iPTH to exert its anabolic activity. Next, we investigated the role of iPTH-stimulated PPR signaling in T cells for the activation of Wnt signaling in osteoblastic cells. To this end, we used the common amplification method of real-time PCR to determine the mRNA expression of genes up-regulated by Wnt signaling. This was analyzed in bone stromal cells purified from PPR T cells−/− and from control mice with functional PPRs, which were treated with iPTH for 4 wk. We found that iPTH activates Wnt signaling in stromal cells through PPR signaling in T cells. This was shown by the increase in mRNA levels after iPTH treatment for all nine tested genes in control mice cells, an increase that did not occur in cells from PPR T cells−/− mice. However, it remains unknown whether direct activation of PPR receptors in T cells by PTH is required for iPTH treatment to exert its full anabolic activity. To address these issues, we have used PPR T cells−/− mice, a strain with a silent or nonactive PPR in all T cells ( 5 ). First, we treated PPR T cells−/− with iPTH for 4 wk. This was done to determine whether the hormone needed T cells with intact receptors, and thus whether the hormone induced T-cell production of Wnt10b by directly targeting T cells. We found that iPTH increased Wnt10b mRNA levels in T cells from control mice. By contrast, PTH had no stimulatory effects in T cells from mutated PPR T cells−/− mice. PTH affects bones by binding to the PTH/parathyroid hormone-related protein receptor (PPR or PTHR1) on bone cells. iPTH stimulates bone formation by increasing the number of osteoblasts, through activation of a specific cell signaling pathway called the Wnt pathway in osteoblastic cells ( 2 ). Although osteoblasts and other bone cells represent the major targets of PTH in bone, reports from our laboratory have disclosed that T lymphocytes play an unexpected role in the mechanism of action of PTH ( 3 – 5 ). We have shown that treatment with iPTH increases the T-cell production of Wnt10b, a Wnt ligand that stimulates osteoblastogenesis by activating Wnt signaling in stromal cells and osteoblasts. As a result, the bone anabolic activity of iPTH is markedly reduced in T cell-deficient mice and in mice with a specific disruption of Wnt10b production by T cells ( 4 ). Parathyroid hormone (PTH) is a major regulator of calcium metabolism; it defends against hypocalcemia, in part, by stimulating bone resorption and thereby the release of calcium from the skeleton. However, when injected daily, a regimen known as intermittent parathyroid hormone (iPTH) treatment, the hormone markedly stimulates bone formation, leading to an increase in bone mass. As a result, intermittent treatment with a form of PTH is a US Food and Drug Administration-approved treatment for postmenopausal osteoporosis ( 1 ).
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1120735109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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