title: Reduced bone mass and muscle strength in male 5α-reductase type 1 inactivated mice.
abstract: Androgens are important regulators of bone mass but the relative importance of testosterone (T) versus dihydrotestosterone (DHT) for the activation of the androgen receptor (AR) in bone is unknown. 5α-reductase is responsible for the irreversible conversion of T to the more potent AR activator DHT. There are two well established isoenzymes of 5α-reductase (type 1 and type 2), encoded by separate genes (Srd5a1 and Srd5a2). 5α-reductase type 2 is predominantly expressed in male reproductive tissues whereas 5α-reductase type 1 is highly expressed in liver and moderately expressed in several other tissues including bone. The aim of the present study was to investigate the role of 5α-reductase type 1 for bone mass using Srd5a1⁻/⁻ mice. Four-month-old male Srd5a1⁻/⁻ mice had reduced trabecular bone mineral density (-36%, p<0.05) and cortical bone mineral content (-15%, p<0.05) but unchanged serum androgen levels compared with wild type (WT) mice. The cortical bone dimensions were reduced in the male Srd5a1⁻/⁻ mice as a result of a reduced cortical periosteal circumference compared with WT mice. T treatment increased the cortical periosteal circumference (p<0.05) in orchidectomized WT mice but not in orchidectomized Srd5a1⁻/⁻ mice. Male Srd5a1⁻/⁻ mice demonstrated a reduced forelimb muscle grip strength compared with WT mice (p<0.05). Female Srd5a1⁻/⁻ mice had slightly increased cortical bone mass associated with elevated circulating levels of androgens. In conclusion, 5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength and we propose that these effects are due to lack of 5α-reductase type 1 expression in bone and muscle. In contrast, the increased cortical bone mass in female Srd5a1⁻/⁻ mice, is an indirect effect mediated by elevated circulating androgen levels.
authors: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors: Sara H
authors: SH
authors: Windahl
authors: Niklas
authors: N
authors: Andersson
authors: Anna E
authors: AE
authors: Börjesson
authors: Charlotte
authors: C
authors: Swanson
authors: Johan
authors: J
authors: Svensson
authors: Sofia
authors: S
authors: Movérare-Skrtic
authors: Klara
authors: K
authors: Sjögren
authors: Ruijin
authors: R
authors: Shao
authors: Marie K
authors: MK
authors: Lagerquist
authors: Claes
authors: C
authors: Ohlsson
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D001842:Bone and Bones / Q000473:pathology* / Q000503:physiopathology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005552:Forelimb / Q000187:drug effects / Q000502:physiology; D020869:Gene Expression Profiling; D018737:Hand Strength / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology*; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011981:Receptors, Prolactin / Q000097:blood / Q000235:genetics; D013739:Testosterone / Q000494:pharmacology; D014781:Viscera / Q000187:drug effects / Q000378:metabolism
chemical_list: D000728:Androgens; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011981:Receptors, Prolactin; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C518406:Srd5a1 protein, mouse