Androgens have antiresorptive effects on trabecular disuse osteopenia independent from muscle atrophy.
Aging hypogonadal men are at increased risk of osteoporosis and sarcopenia. Testosterone is a potentially appealing strategy to prevent simultaneous bone and muscle loss. The androgen receptor (AR) mediates antiresorptive effects on trabecular bone via osteoblast-lineage cells, as well as muscle-anabolic actions. Sex steroids also modify the skeletal response to mechanical loading. However, it is unclear whether the effects of androgens on bone remain effective independent of mechanical stimulation or rather require indirect androgen effects via muscle. This study aims to characterize the effects and underlying mechanisms of androgens on disuse osteosarcopenia. Adult male mice received a unilateral botulinum toxin (BTx) injection, and underwent sham surgery or orchidectomy (ORX) without or with testosterone (ORX+T) or dihydrotestosterone (ORX+DHT) replacement. Compared to the contralateral internal control hindlimb, acute trabecular number and bone volume loss was increased by ORX and partially prevented DHT. T was more efficient and increased BV/TV in both hindlimbs over sham values, although it did not reduce the detrimental effect of BTx. Both androgens and BTx regulated trabecular osteoclast surface as well as tartrate-resistant acid phosphatase expression. Androgens also prevented BTx-induced body weight loss but did not significantly influence paralysis or muscle atrophy. BTx and ORX both reduced cortical thickness via endosteal expansion, which was prevented by T but not DHT. In long-term follow-up, the residual trabecular bone volume deficit in sham-BTx hindlimbs was prevented by DHT but T restored it more efficiently to pre-treatment levels. Conditional AR deletion in late osteoblasts and osteocytes or in the satellite cell lineage increased age-related trabecular bone loss in both hindlimbs without influencing the effect of BTx on trabecular osteopenia. We conclude that androgens have antiresorptive effects on trabecular disuse osteopenia which do not require AR actions on bone via muscle or via osteocytes.
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 901, 3000 Leuven, Belgium; Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven, Herestraat 49, PO box 7003, 3000 Leuven, Belgium; Center for Metabolic Bone Diseases, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: michael.laurent@kuleuven.be.
Michaël R
MR
Laurent
Clinical and Experimental Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 902, 3000 Leuven, Belgium. Electronic address: ferran.jardi@kuleuven.be.
Ferran
F
Jardí
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 901, 3000 Leuven, Belgium. Electronic address: vanessa.dubois@inserm.fr.
Vanessa
V
Dubois
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 901, 3000 Leuven, Belgium. Electronic address: dieter.schollaert@kuleuven.be.
Dieter
D
Schollaert
Clinical and Experimental Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 902, 3000 Leuven, Belgium. Electronic address: rougin.khalil@kuleuven.be.
Rougin
R
Khalil
Gerontology and Geriatrics, Department of Clinical and Experimental Medicine, KU Leuven, Herestraat 49, PO box 7003, 3000 Leuven, Belgium; Center for Metabolic Bone Diseases, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: evelien.gielen@uzleuven.be.
Evelien
E
Gielen
Clinical and Experimental Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 902, 3000 Leuven, Belgium. Electronic address: geert.carmeliet@kuleuven.be.
Geert
G
Carmeliet
Laboratory of Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 901, 3000 Leuven, Belgium. Electronic address: frank.claessens@kuleuven.be.
Frank
F
Claessens
Clinical and Experimental Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Herestraat 49, PO box 902, 3000 Leuven, Belgium. Electronic address: dirk.vanderschueren@uzleuven.be.
Dirk
D
Vanderschueren
D000208:Acute Disease; D000728:Androgens / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002113:Calcification, Physiologic; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009133:Muscular Atrophy / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020966:Muscular Disorders, Atrophic / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D017570:MyoD Protein / Q000378:metabolism; D009929:Organ Size; D011944:Receptors, Androgen / Q000378:metabolism; D055114:X-Ray Microtomography
D000728:Androgens; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D017570:MyoD Protein; D011944:Receptors, Androgen; C045073:Cre recombinase; D019426:Integrases
Androgen receptor; Androgens; Conditional knock-out mice; Disuse osteoporosis; Muscle; Testosterone