Summary Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis as it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells, and induces these lymphocytes to activate canonical Wnt-signaling in pre-osteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in pre-osteoblasts and blunted osteoblastic commitment, proliferation, differentiation and lifespan which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T cell produced Wnt10b. Therefore, T cell mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast cross-talk pathways may provide pharmacological targets for bone anabolism.

Intermittent parathyroid hormone (iPTH) treatment stimulates Tcell production of the osteogenic Wnt ligand Wnt10b, a factor required for iPTH to activate Wnt signaling in osteoblasts and stimulate bone formation. However, it is unknown whether iPTH induces Wnt10b production and bone anabolism through direct activation of the parathyroid hormone (PTH)/PTH-related protein receptor (PPR) in T cells. Here, we show that conditional silencing of PPR in T cells blunts the capacity of iPTH to induce T-cell production of Wnt10b; activate Wnt signaling in osteoblasts; expand the osteoblastic pool; and increase bone turnover, bone mineral density, and trabecular bone volume. These findings demonstrate that direct PPR signaling in T cells plays an important role in PTH-induced bone anabolism by promoting T-cell production of Wnt10b and suggest that T cells may provide pharmacological targets for bone anabolism.bone mass | T lymphocytes | bone cells P arathyroid hormone (PTH) is a major regulator of calcium metabolism and 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 trabecular and cortical bone formation. Although this bone-forming activity is antagonized by a stimulation of bone resorption, the net effect of iPTH treatment is an improvement in bone microarchitecture and increased strength (1, 2). As a result, intermittent treatment with the 1-34 fragment of PTH is a Food and Drug Administration-approved treatment modality for postmenopausal osteoporosis (3).The effects of PTH on bone result from its binding to the PTH/PTH-related protein receptor (PPR or PTHR1) expressed on bone marrow (BM), stromal cells (SCs), osteoblasts (OBs), and osteocytes (1, 4, 5). iPTH stimulates bone formation by increasing the number of OBs (6-8), a phenomenon achieved through activation of quiescent lining cells (9), increased OB proliferation (10, 11) and differentiation (10, 12, 13), attenuation of OB apoptosis (14-17), and signaling in osteocytes (18). However, the specific contribution of each of these effects of iPTH remains controversial. The expansion of the osteoblastic pool induced by iPTH is initiated by the release from the matrix undergoing resorption of TGF-β, insulin-like growth factor 1, and other growth factors that recruit SCs to remodeling areas (19)(20)(21)(22). Subsequent events are driven primarily by the activation of Wnt signaling in osteoblastic cells (23). Activation of Wnt signaling induces OB proliferation (24) and differentiation (23, 25), prevents OB apoptosis (16,17,26), and augments OB production of osteoprotegerin (OPG) (27).iPTH activates Wnt signaling in OBs through multiple mechanisms that include Wnt ligand-independent activation of the Wnt coreceptor LRP6 (28), increased production of Wnt ligands by bone and BM cells (29,30), and suppression of sclerostin production (31-33). Additional effects on the ...

Previous studies have identified the DUB family of cytokine-regulated murine deubiquitinating enzymes, which play a role in the control of cell proliferation and survival. Through data base analyses and cloning, we have identified a human cDNA (DUB-3) that shows significant homology to the known murine DUB family members. Northern blotting has shown expression of this gene in a number of tissues including brain, liver, and muscle, with two transcripts being apparent (1.6 and 1.7 kb). In addition, expression was observed in cell lines including those derived from a number of hematopoietic tumors such as the Burkitt's lymphoma cell line RAJI. We have also demonstrated that DUB-3, which was shown to be an active deubiquitinating enzyme, is induced in response to interleukin-4 and interleukin-6 stimulation. Finally, we have demonstrated that constitutive expression of DUB-3 blocks proliferation and can initiate apoptosis in both IL-3-dependent Ba/F3 cells and NIH3T3 fibroblasts. These findings suggest that human DUB-3, like the murine DUB family members, is transiently induced in response to cytokines and can, when constitutively expressed, block growth factor-dependent proliferation.

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