Altered TNSALP expression and phosphate regulation contribute to reduced mineralization in mice lacking androgen receptor.
While androgen receptor (AR)-deficient mice developed osteopenia in endochondral bones due to the high bone turnover with increased bone resorption by osteoclasts, little is known about the mechanism of intramembranous bone loss contributed by AR in osteoblasts. Here, we discovered a dramatic decrease in the area of calcification, new bone, and the number of osteocytes in calvaria from AR-deficient mice related to a reduction in mineralization caused, in part, by the diminished activity of AR-deficient osteoblasts. Enforced AR expression in differentiated osteoblasts boosts mineralization while knockdown of AR expression prevents androgen-induced mineralization. We identified the tissue-nonspecific alkaline phosphatase (TNSALP) and several members of small integrin binding ligand N-linked glycoprotein (SIBLING) gene family as androgen target genes required for AR-mediated bone formation. We show that inorganic phosphate (P(i)) levels and TNSALP activity increased in response to androgen/AR and P(i) signals increase the expression and translocation of AR. The ectopic expression of TNSALP or P(i) partially rescued the bone loss due to AR deficiency. Thus, androgen/AR signaling plays an essential role in bone formation by coordinating the expression of genes associated with phosphate regulation.
Kang
Hong-Yo
HY
Center for Menopause and Reproductive Medicine Research, Chang Gung University, Chang Gung Memorial Hospital, 12F, No. 123, Ta Pei Rd., Niao Sung Hsiang, Kaohsiung 833, Taiwan.
Shyr
Chih-Rong
CR
Huang
Chiung-Kuei
CK
Tsai
Meng-Yin
MY
Orimo
Hideo
H
Lin
Pei-Chun
PC
Chang
Chawnshang
C
Huang
Ko-En
KE
D016475:3T3 Cells; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010710:Phosphates / Q000378:metabolism*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012886:Skull / Q000033:anatomy & histology / Q000502:physiology
D000728:Androgens; D007527:Isoenzymes; D010710:Phosphates; D011944:Receptors, Androgen; C510878:ALPL protein, mouse; D000469:Alkaline Phosphatase