title: Testosterone regulates bone response to inflammation.
abstract: This study evaluated the alveolar bone response to testosterone and the impact of Resolvin D2 (RvD2) on testosterone-induced osteoblast function. For the in vivo characterization, 60 male adult rats were used. Treatments established sub-physiologic (L), normal (N), or supra-physiologic (H) concentrations of testosterone. Forty rats were subjected to orchiectomy; 20 rats received periodical testosterone injections while 20 rats received testicular sham-operation. Four weeks after the surgeries, 10 rats in each group received a subgingival ligature around the lower first molars to induce experimental periodontal inflammation and bone loss. In parallel, osteoblasts were differentiated from neonatal mice calvariae and treated with various doses of testosterone for 48 h. Cell lysates and conditioned media were used for the determination of alkaline phosphatase, osteocalcin, RANKL, and osteoprotegerin. Micro-computed tomography linear analysis demonstrated that bone loss was significantly increased for both L and H groups compared to animals with normal levels of testosterone. Gingival IL-1β expression was increased in the L group (p<0.05). Ten nM testosterone significantly decreased osteocalcin, RANKL, and OPG levels in osteoblasts; 100 nM significantly increased the RANKL:OPG ratio. RvD2 partially reversed the impact of 10 nM testosterone on osteocalcin, RANKL, and OPG. These findings suggest that both L and H testosterone levels increase inflammatory bone loss in male rats. While low testosterone predominantly increases the inflammatory response, high testosterone promotes a higher osteoblast-derived RANKL:OPG ratio. The proresolving mediator RvD2 ameliorates testosterone-derived downregulation of osteocalcin, RANKL, and OPG in primary murine osteoblasts suggesting a direct role of inflammation in osteoblast function.
authors: Department of Physiology and Pathology, School of Dentistry at Araraquara - UNESP, São Paulo State University, -Araraquara, SP, Brazil.
authors: J P
authors: JP
authors: Steffens
authors: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA.
authors: B S
authors: BS
authors: Herrera
authors: Department of Physiology and Pathology, School of Dentistry at Araraquara - UNESP, São Paulo State University, -Araraquara, SP, Brazil.
authors: L S
authors: LS
authors: Coimbra
authors: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA.
authors: D N
authors: DN
authors: Stephens
authors: Department of Physiology and Pathology, School of Dentistry at Araraquara - UNESP, São Paulo State University, -Araraquara, SP, Brazil.
authors: C
authors: C
authors: Rossa
authors: Department of Physiology and Pathology, School of Dentistry at Araraquara - UNESP, São Paulo State University, -Araraquara, SP, Brazil.
authors: L C
authors: LC
authors: Spolidorio
authors: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA.
authors: A
authors: A
authors: Kantarci
authors: Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA.
authors: T E
authors: TE
authors: Van Dyke
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D010510:Periodontal Diseases / Q000097:blood; D053245:RANK Ligand / Q000378:metabolism; D051381:Rats; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*; D055114:X-Ray Microtomography
chemical_list: D016207:Cytokines; D053244:Osteoprotegerin; D053245:RANK Ligand; C545423:resolvin D2; D015675:Osteocalcin; D004281:Docosahexaenoic Acids; D013739:Testosterone; D000469:Alkaline Phosphatase