Abstract
Osteoporosis is an age-related disorder of bone remodeling in which bone resorption outstrips bone matrix deposition. Although anticatabolic agents are frequently used as first-line therapies for osteoporosis, alternative anabolic strategies that can enhance anabolic, osteogenic potential are actively sought. Sex steroid hormones, particularly estrogens, are bidirectional regulators for bone homeostasis; therefore, estrogen-mediated events are important potential targets for such anabolic therapies. Here, we show that estrogen-induced, osteoanabolic effects were mediated via enhanced production of chondroitin sulfate-E (CS-E), which could act as an osteogenic stimulant in our cell-based system. Conversely, estrogen deficiency caused reduced expression of CS-E-synthesizing enzymes, including GalNAc4S-6ST, and led to decreased CS-E production in cultures of bone marrow cells derived from ovariectomized mice. Moreover, Galnac4s6st-deficient mice had abnormally low bone mass that resulted from impaired osteoblast differentiation. These results indicated that strategies aimed at boosting CS-E biosynthesis are promising alternative therapies for osteoporosis.
Highlights
Osteoporosis is an age-related disorder of bone remodeling in which bone resorption outstrips bone matrix deposition
We show that estrogen-induced, osteoanabolic effects were mediated via enhanced production of chondroitin sulfate-E (CS-E), which could act as an osteogenic stimulant in our cell-based system
After a 24-h exposure to estradiol, when individual cells remained dispersed, Chondroitin sulfate (CS) isolated from MC3T3-E1 cultures was depolymerized with a bacterial CS-degrading enzyme, chondroitinase ABC (ChABC), and resultant CS disaccharides were analyzed via high-performance liquid chromatography (Table 1)
Summary
Osteoporosis is an age-related disorder of bone remodeling in which bone resorption outstrips bone matrix deposition. Estrogens, are bidirectional regulators for bone homeostasis; estrogen-mediated events are important potential targets for such anabolic therapies. Galnac4s6st-deficient mice had abnormally low bone mass that resulted from impaired osteoblast differentiation These results indicated that strategies aimed at boosting CS-E biosynthesis are promising alternative therapies for osteoporosis. Unraveling the distinctive mechanisms of action during estrogen-mediated bone formation is important for development of more effective anabolic therapies for osteoporosis. Plasma and tissue levels of CS, like serum levels of estrogens, gradually decrease with age[25,26,27,28,29,30] These apparently functional similarities between CS and estrogens indicate that particular CS biosynthetic pathways are critical targets for www.nature.com/scientificreports estrogen-mediated cellular events, including osteoblastic bone formation. We aimed to test whether osteoanabolic activities of estrogens are exerted via CS-E production
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