Androgen prevents hypogonadal bone loss via inhibition of resorption mediated by mature osteoblasts/osteocytes

Abstract

Androgen receptor (AR) is expressed throughout the osteoblast lineage. Two different AR transgenic families (AR2.3-tg and AR3.6-tg mice) demonstrating overlapping and distinct expression profiles were employed to assess the effects of enhanced androgen sensitivity to ameliorate hypogonadal loss. Two different paradigms of steroid replacement following orchidectomy (ORX) were used as either preventative or therapeutic therapy. ORX was performed in male wild-type (WT), AR2.3-tg and AR3.6-tg mice at 5 months with immediate DHT replacement (prevention, higher turnover) or at 3 months with DHT treatment delayed for 2 months (therapeutic, lower turnover), both with treatment for the last 6 weeks. Dual energy x-ray absorptiometry (DXA), microcomputed tomography (μCT), and histomorphometry were performed. In the prevention model, ORX significantly reduced BMD and BMC in all genotypes compared to sham and DHT was effective at prevention of osteopenia. In the therapeutic model, all genotypes became osteopenic compared to sham, but after a prolonged hypogonadal period, delayed DHT treatment provided little benefit. μCT analysis of mid-shaft total bone in all genotypes generally showed reductions after ORX. Delayed DHT was ineffective at restoring bone volume in any genotype whereas immediate treatment prevented loss only in AR transgenic mice. Cortical thickness also decreased with ORX but immediate DHT treatment was effective to increase thickness only in WT mice, likely due to expansion of marrow volume in both AR-tg lines. In metabolically highly active cancellous bone, ORX resulted in lower bone volume/tissue volume (BV/TV) in all genotypes, consistent among 3 sites measured. Again with delayed treatment, there was little effect of DHT to restore BV/TV, but when administered at the time of ORX, DHT completely prevented the decrease in cancellous bone in all genotypes. Improvement in cancellous bone architecture was seen with immediate DHT replacement that was enhanced in AR transgenic lines compared to WT. In contrast, there were only modest changes in all genotypes using the delayed treatment paradigm. With ORX in both paradigms, trabecular number was decreased while spacing increased. Thus, androgen therapy is effective for the prevention of endosteal and cancellous osteopenia primarily through its anti-resorptive properties, but shows little anabolic action as a therapeutic strategy to restore bone. Given the similarity in response to androgen treatment in both AR transgenic lines, overlapping expression profiles suggest that the target cells mediating androgen action in vivo are mature osteoblast/osteocytes. Combined, these results demonstrate that in the adult mouse, androgen treatment can reduce bone resorption but has little overall anabolic activity.

Androgen Receptor Action in Osteoblasts in Male Mice Is Dependent on Their Stage of Maturation

“…Furthermore, because the response to DHT was similar in both AR transgenic lines, this suggests that the inhibitory actions of androgens on bone resorption are mediated via the AR in mineralizing osteoblasts and/or osteocytes. (27) Expanding these findings, we now demonstrate that androgens also exert their inhibitory actions on bone resorption via the AR in a more immature population of proliferating osteoblasts during trabecular bone accrual and modelling during growth. This action of the AR in proliferating osteoblasts within trabecular bone to inhibit bone resorption during rapid growth and remodeling is consistent with previous observations that a higher number of cartilage fragments are retained from early in development in mice overexpressing the AR in proliferating osteoblasts (Col3.6AR-tg) compared with control mice, most likely the result of impaired bone resorption.…”

“…This action of the AR in proliferating osteoblasts within trabecular bone to inhibit bone resorption during rapid growth and remodeling is consistent with previous observations that a higher number of cartilage fragments are retained from early in development in mice overexpressing the AR in proliferating osteoblasts (Col3.6AR-tg) compared with control mice, most likely the result of impaired bone resorption. (27) The mechanism by which the AR in osteoblasts inhibits bone resorption is at least in part because of the downregulation of RANKL expression by osteoblasts. (10) In the present study, replacement of the AR in proliferating osteoblasts of Global-ARKOs attenuated their increased RANKL/OPG mRNA to levels observed in WT control mice, thereby suppressing osteoclastogenesis and returning osteoclast numbers and bone resorption rates to normal.…”

“…(26) In addition, DHT treatment in both Col3.6AR-tg and Col2.3AR-tg mice prevents trabecular bone loss after orchidectomy by inhibiting bone resorption, indicating that the target cells responsible for mediating this response are likely to be mineralizing osteoblasts and/or osteocytes. (27) To test these hypotheses and to elucidate the mechanism of androgens acting directly via the AR in osteoblasts to regulate their maturation and activity, we have generated defined osteoblast-AR gene replacement models, in which the AR is specifically replaced in the osteoblasts of Global-ARKO mice at defined stages of osteoblast maturation, commencing at either the 1) proliferative or 2) mineralization stage. A unique feature of the pOBL-AR and mOBL-AR gene replacement mice is that they inherit the X chromosome (on which the mutant AR gene is located) from their Global-ARKO mother and, therefore, do not express endogenous AR in any tissue.…”

2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013

“…Testosterone replacement: The other gonadal hormone that is low in conditions of low weight and in amenorrhoeic athletes and exercising women is testosterone, which has antiresorptive effects (direct and oestrogen mediated)186 187 and also bone anabolic effects 187 188. There are no data available on testosterone administration in amenorrhoeic athletes and exercising women.…”

Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health

“…Murine models with osteocyte-specific androgen receptor knockout have demonstrated decreases in trabecular bone volume and trabeculae number, and these decreases worsened with age [60]. Two additional mouse lines with osteocyte-specific androgen receptor knockout showed the role of the androgen receptor in prevention of age-related trabecular bone loss but not anabolic bone formation [61]. Overall this suggests that the androgen receptor in osteocytes is important for age-related prevention of trabecular bone resorption.…”