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Horm Metab Res 2014; 46(03): 193-200
DOI: 10.1055/s-0034-1367031
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Testosterone Regulates Bone Response to Inflammation

J. P. Steffens
1   Department of Physiology and Pathology, School of Dentistry at Araraquara – UNESP, São Paulo State University, ­Araraquara, SP, Brazil
2   Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA
,
B. S. Herrera
2   Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA
,
L. S. Coimbra
1   Department of Physiology and Pathology, School of Dentistry at Araraquara – UNESP, São Paulo State University, ­Araraquara, SP, Brazil
,
D. N. Stephens
2   Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA
,
C. Rossa Jr
1   Department of Physiology and Pathology, School of Dentistry at Araraquara – UNESP, São Paulo State University, ­Araraquara, SP, Brazil
,
L. C. Spolidorio
1   Department of Physiology and Pathology, School of Dentistry at Araraquara – UNESP, São Paulo State University, ­Araraquara, SP, Brazil
,
A. Kantarci
2   Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA
,
T. E. Van Dyke
2   Department of Applied Oral Sciences, Center for Periodontology, The Forsyth Institute, Cambridge, MA, USA
› Author Affiliations
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Publication History

received 10 July 2013

accepted 06 January 2014

Publication Date:
13 February 2014 (online)

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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.

Key words

testosterone - osteoblasts - docosahexaenoic acids - RANK ligand - osteocalcin - osteoprotegerin