Osteoblast and osteocyte apoptosis associated with androgen action in bone: Requirement of increased Bax/Bcl-2 ratio

Wiren, Kristine M.; Toombs, Amber R.; Semirale, Anthony A.; Zhang, Xiaowei

doi:10.1016/j.bone.2005.10.029

Cited by 82 publications

(61 citation statements)

References 65 publications

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“…Transient administration of nonaromatizable DHT can enhance transcription factor activation and osteoblast proliferation, while chronic treatment inhibits both mitogenic signaling and MAP kinase activity [66]. Chronic DHT treatment in vitro can also enhance osteoblast apoptosis [65]. Combined, these in vitro reports are consistent with the detrimental changes in matrix quality and osteoblast vigor we observe in the AR-transgenic model in vivo.…”

Section: Discussionsupporting

confidence: 76%

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

Wiren

Semirale

Zhang

et al. 2008

Bone

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Androgens are anabolic hormones that affect many tissues, including bone. However, an anabolic effect of androgen treatment on bone in eugonadal subjects has not been observed and clinical trials have been disappointing. The androgen receptor (AR) mediates biological responses to androgens. In bone tissue, both AR and the estrogen receptor (ER) are expressed. Since androgens can be converted into estrogen, the specific role of the AR in maintenance of skeletal homoeostasis remains controversial. The goal of this study was to use skeletally targeted overexpression of AR in differentiated osteoblasts as a means of elucidating the specific role(s) for AR transactivation in the mature bone compartment. Transgenic mice overexpressing AR under the control of the 2.3-kb α1 (I)-collagen promoter fragment showed no difference in body composition, testosterone, or 17β-estradiol levels. However, transgenic males have reduced serum osteocalcin, CTx and TRAPC5b levels, and a bone phenotype was observed. In cortical bone, high-resolution micro-computed tomography revealed no difference in periosteal perimeter but a significant reduction in cortical bone area due to an enlarged marrow cavity. Endocortical bone formation rate was also significantly inhibited. Biomechanical analyses showed decreased whole bone strength and quality, with significant reductions in all parameters tested. Trabecular morphology was altered, with increased bone volume comprised of more trabeculae that were closer together but not thicker. Expression of genes involved in bone formation and bone resorption was significantly reduced. The consequences of androgen action are compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibited osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength. Thus, the present data demonstrate that enhanced androgen signaling targeted to bone results in low bone turnover and inhibition of bone formation by differentiated osteoblasts. These results indicate that direct androgen action in mature osteoblasts is not anabolic, and raise concerns regarding anabolic steroid abuse in the developing skeleton or high-dose treatment in eugonadal adults.

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Section: Discussionsupporting

confidence: 76%

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

Wiren

Semirale

Zhang

et al. 2008

Bone

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Section: Discussionsupporting

confidence: 75%

Enhanced Androgen Signaling with Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

Wiren¹,

Turner²

2008

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTAndrogens have been shown to be important mediators of bone growth and remodeling independent of estrogen. We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone. In the fourth year, we have published the analysis of the second line of AR-transgenic mice, AR2.3-transgenic mice. Enhanced androgen signaling directly in bone results in inhibition of bone formation by differentiated osteoblasts, with a phenotype reflecting low turnover. Comparisons between both models of AR2.3-and AR3.6-transgenic animals suggests that AR transactivation in osteocytes is primarily responsible for mediating the effects of androgen on matrix quality and/or mineralization (inhibitory), while stromal/immature cells mediate effects of androgen on the periosteum and body composition (anabolic). The consequence of androgen action in vivo is compartment-specific; anabolic effects are exhibited exclusively at periosteal surfaces, but in mature osteoblasts androgens inhibit osteogenesis with detrimental effects on matrix quality, bone fragility and whole bone strength (Specific Aim 1). Gene expression profiling has identified important signaling pathways by which androgens influence osteoblast-osteoclast communication (Specific aim 2). With immediate androgen replacement during a sustained hypogonadal period, gender differences are observed in the response to androgen replacement: both males and females demonstrate improved bone mineral, but female AR-transgenic mice are insensitive to improvements. These results indicate that direct androgen is generally not anabolic in the skeleton. Gene expression analysis of androgen action in endocortical bone and differentiation in calvarial cultures from AR2.3-tg mice (Specific aim 3) are ongoing. Results indicate regulation of genes involved in osteoblast differentiation that may be detrimental. SUBJECT TERMS

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“…Several studies have demonstrated that testosterone played an important role in osteoblastic proliferation by enhancing mitogenesis and differentiation in bone cells (Sömjen et al 1989, Kasperk et al 1990, Gray et al 1992. In addition, testosterone has been shown to play a role in osteoblast apoptosis in which a lack of testosterone enhanced osteoblast apoptosis through an increased Bax/Bcl-2 ratio (Wiren et al 2006. Our results showed that a reduction of the Gla/Glu osteocalcin ratio, decreased osteoblastic proliferation and increased osteoblastic apoptosis in testosterone-deprived rats was associated with microstructural changes in the tibial trabecular bones and a significant overall reduction in mineral density of those bones.…”

Section: Discussionmentioning

confidence: 99%

Obesity does not aggravate osteoporosis or osteoblastic insulin resistance in orchiectomized rats

Potikanond¹,

Rattanachote²,

Pintana³

et al. 2016

Journal of Endocrinology

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The present study aimed to test the hypothesis that testosterone deprivation impairs osteoblastic insulin signaling, decreases osteoblast survival, reduces bone density, and that obesity aggravates those deleterious effects in testosterone-deprived rats. Twenty four male Wistar rats underwent either a bilateral orchiectomy (O, nZ12) or a sham operation (S, nZ12). Then the rats in each group were further divided into two subgroups fed with either a normal diet (ND) or a high-fat diet (HF) for 12 weeks. At the end of the protocol, blood samples were collected to determine metabolic parameters and osteocalcin ratios. The tibiae were collected to determine bone mass using microcomputed tomography and for osteoblast isolation. The results showed that rats fed with HF (sham-operated HF-fed rats (HFS) and ORX HF-fed rats (HFO)) developed peripheral insulin resistance and had decreased trabecular bone density. In ND-fed rats, only the ORX ND-fed rats (NDO) group had decreased trabecular bone density. In addition, osteoblastic insulin resistance, as indicated by a decrease in tyrosine phosphorylation of the insulin receptor and Akt, were observed in all groups except the sham-operated ND-fed rats (NDS) rats. Those groups, again with the exception of the NDS rats, also had decreased osteoblastic survival. No differences in the levels of osteoblastic insulin resistance and osteoblastic survival were found among the NDO, HFS, and HFO groups. These findings suggest that either testosterone deprivation or obesity alone can impair osteoblastic insulin signaling and decrease osteoblastic survival leading to the development of osteoporosis. However, obesity does not aggravate those deleterious effects in the bone of testosterone-deprived rats.

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Osteoblast and osteocyte apoptosis associated with androgen action in bone: Requirement of increased Bax/Bcl-2 ratio

Cited by 82 publications

References 65 publications

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

Enhanced Androgen Signaling with Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

Obesity does not aggravate osteoporosis or osteoblastic insulin resistance in orchiectomized rats

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