Phosphorylation of S122 in ERα is important for the skeletal response to estrogen treatment in male mice

• Published in: Scientific reports Vol. 12; no. 1; p. 22449
• Main Authors: Horkeby, Karin, Farman, Helen H., Movérare-Skrtic, Sofia, Lionikaite, Vikte, Wu, Jianyao, Henning, Petra, Windahl, Sara, Sjögren, Klara, Ohlsson, Claes, Lagerquist, Marie K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 17β-Estradiol; 692/163; 692/163/2743/316/801; Animals; Body Weight; Bone and Bones - diagnostic imaging; Bone and Bones - metabolism; Bone mineral density; Cancellous bone; Child; Cortical bone; Endocrinology and Diabetes; Endokrinologi och diabetes; Estradiol; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Estrogens - pharmacology; Humanities and Social Sciences; Humans; Infant; Male; Males; Medicin och hälsovetenskap; Mice; multidisciplinary; Osteoporosis; Phosphorylation; Science; Science (multidisciplinary); Skeleton; Tibia; Tissues
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-26939-9

Estrogen receptor alpha (ERα) signaling has beneficial skeletal effects in males. ERα signaling also affects other tissues, and to find bone-specific treatments, more knowledge regarding tissue-specific ERα signaling is needed. ERα is subjected to posttranslational modifications, including phosphorylation, which can influence ERα function in a tissue-specific manner. To determine the importance of phosphorylation site S122 (corresponding to human ERα site S118) for the skeleton and other tissues, male mice with a S122A mutation were used. Total areal bone mineral density was similar between gonadal intact S122A and WT littermates followed up to 12 months of age, and weights of estrogen-responsive organs normalized for body weight were unchanged between S122A and WT males at both 3 and 12 months of age. Interestingly, 12-month-old S122A males had decreased body weight compared to WT. To investigate if site S122 affects the estrogen response in bone and other tissues, 12-week-old S122A and WT males were orchidectomized (orx) and treated with estradiol (E2) or placebo pellets for four weeks. E2 increased cortical thickness in tibia in both orx WT (+ 60%, p < 0.001) and S122A (+ 45%, p < 0.001) males. However, the E2 effect on cortical thickness was significantly decreased in orx S122A compared to WT mice (− 24%, p < 0.05). In contrast, E2 affected trabecular bone and organ weights similarly in orx S122A and WT males. Thus, ERα phosphorylation site S122 is required for a normal E2 response specifically in cortical bone in male mice, a finding that may have implications for development of future treatments against male osteoporosis.