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PDE inhibitors increase bone formation and bone mass in preclinical models and are used clinically to treat psoriatic arthritis by targeting inflammatory mediators including activated T cells. T cell activation requires two signals: antigen\u2010dependent CD3\u2010activation, which stimulates cAMP production; and CD28 co\u2010stimulation, which downregulates cAMP\u2010signaling, through PDE activation. PDE\u2010inhibitors consequently suppress T cell activation by disrupting CD28 co\u2010stimulation. Interestingly, we have reported that when CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells are activated in the absence of CD28 co\u2010stimulation, they secrete Wnt\u201010b, a bone anabolic Wnt ligand that promotes bone formation. In the present study, we investigated whether the bone anabolic activity of the PDE\u2010inhibitor PTX, has an immunocentric basis, involving Wnt\u201010b production by CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. When wild\u2010type (WT) mice were administered PTX, biochemical markers of both bone resorption and formation were significantly increased, with net bone gain in the axial skeleton, as quantified by micro\u2010computed tomography (\u03bcCT). By contrast, PTX increased only bone resorption in T cell knockout (KO) mice, causing net bone loss. Reconstituting T cell\u2013deficient mice with WT, but not Wnt\u201010b knockout (KO) CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, rescued bone formation and prevented bone loss. To study the role of cAMP signaling in Wnt\u201010b expression, reverse\u2010transcription polymerase chain reaction (RT\u2010PCR) and luciferase\u2010reporter assays were performed using primary T cells. PDE inhibitors intensified Wnt\u201010b promoter activity and messenger RNA (mRNA) accumulation in CD3 and CD28 activated CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. In contrast, inhibiting the cAMP pathway mediators protein kinase A (PKA) and cAMP response element\u2010binding protein (CREB), suppressed Wnt\u201010b expression by T cells activated in the absence of CD28 co\u2010stimulation. In conclusion, the data demonstrate a key role for Wnt\u201010b production by CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in the bone anabolic response to PDE\u2010inhibitors and reveal competing T cell\u2013independent pro\u2010resorptive properties of PTX, which dominate under T cell\u2013deficient conditions. Selective targeting of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells by PDE inhibitors may be a beneficial approach for promoting bone regeneration in osteoporotic conditions. \u00a9 2022 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10636","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T11:34:56Z","timestamp":1652700896000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cyclic Adenosine Monophosphate (cAMP)\u2010Dependent Phosphodiesterase Inhibition Promotes Bone Anabolism Through\n                    <scp>CD8<\/scp>\n                    <sup>+<\/sup>\n                    T Cell Wnt\u201010b Production in Mice"],"prefix":"10.1093","volume":"6","author":[{"given":"Susanne","family":"Roser\u2010Page","sequence":"first","affiliation":[{"name":"Atlanta Department of Veterans Affairs Medical Center  Decatur GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiana","family":"Weiss","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism and Lipids, Department of Medicine Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Vikulina","sequence":"additional","affiliation":[{"name":"Atlanta Department of Veterans Affairs Medical Center  Decatur GA USA"},{"name":"Division of Endocrinology and Metabolism and Lipids, Department of Medicine Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingcan","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism and Lipids, Department of Medicine Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6077-8250","authenticated-orcid":false,"given":"Roberto","family":"Pacifici","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism and Lipids, Department of Medicine Emory University School of Medicine  Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3305-5748","authenticated-orcid":false,"given":"M. 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