Cyclic Adenosine Monophosphate (cAMP)-Dependent Phosphodiesterase Inhibition Promotes Bone Anabolism Through CD8⁺ T Cell Wnt-10b Production in Mice

• Authors: Susanne Roser-Page, Atlanta VA Medical Center; Daiana Weiss, Emory University; Tatyana Vikulina, Atlanta VA Medical Center; Mingcan Yu, Emory University; Roberto Pacifici, Emory University; M. Neale Weitzmann, Emory University
• Journal Title: JBMR Plus
• Volume: Volume 6, Number 7
• Publisher: Wiley Periodicals LLC | 2022-07-01, Pages e10636-e10636
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/jbm4.10636
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: ANABOLICS; CELLS OF BONE; OSTEOBLASTS; OSTEOIMMUNOLOGY; SYSTEMS BIOLOGY–BONE INTERACTORS; THERAPEUTICS

Abstract

Cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) inhibitors such as pentoxifylline (PTX) suppress cAMP degradation and promote cAMP-dependent signal transduction. 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-dependent CD3-activation, which stimulates cAMP production; and CD28 co-stimulation, which downregulates cAMP-signaling, through PDE activation. PDE-inhibitors consequently suppress T cell activation by disrupting CD28 co-stimulation. Interestingly, we have reported that when CD8+ T cells are activated in the absence of CD28 co-stimulation, they secrete Wnt-10b, a bone anabolic Wnt ligand that promotes bone formation. In the present study, we investigated whether the bone anabolic activity of the PDE-inhibitor PTX, has an immunocentric basis, involving Wnt-10b production by CD8+ T cells. When wild-type (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-computed tomography (μCT). By contrast, PTX increased only bone resorption in T cell knockout (KO) mice, causing net bone loss. Reconstituting T cell–deficient mice with WT, but not Wnt-10b knockout (KO) CD8+ T cells, rescued bone formation and prevented bone loss. To study the role of cAMP signaling in Wnt-10b expression, reverse-transcription polymerase chain reaction (RT-PCR) and luciferase-reporter assays were performed using primary T cells. PDE inhibitors intensified Wnt-10b promoter activity and messenger RNA (mRNA) accumulation in CD3 and CD28 activated CD8+ T cells. In contrast, inhibiting the cAMP pathway mediators protein kinase A (PKA) and cAMP response element-binding protein (CREB), suppressed Wnt-10b expression by T cells activated in the absence of CD28 co-stimulation. In conclusion, the data demonstrate a key role for Wnt-10b production by CD8+ T cells in the bone anabolic response to PDE-inhibitors and reveal competing T cell–independent pro-resorptive properties of PTX, which dominate under T cell–deficient conditions. Selective targeting of CD8+ T cells by PDE inhibitors may be a beneficial approach for promoting bone regeneration in osteoporotic conditions. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.