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Chondroitin sulfate-E mediates estrogen-induced osteoanabolism.

Koike T, Mikami T, Shida M, Habuchi O, Kitagawa H - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Biosynthetic machinery for CS-E production is affected by estrogen depletion.(a,b) Expression of mRNAs encoding CHSTs (C4st1, C4st2, C6st1, or Galnac4s6st in a), and ChGns (Csgalnact1 or Csgalnact2 in b) in BMSCs isolated from 14-week-old WT female mice that were sham-operated (Sham) or ovariectomized (OVX) at 8 weeks of age. (n = 3 cultures, each from an independent mouse). Data are represented as mean ± s.d. *, P < 0.05. (c) μCT analysis of tibias of mice in a (n = 3 mice per group). BMD, bone mineral density. Data are represented as mean ± s.d. ***, P < 0.001.
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f2: Biosynthetic machinery for CS-E production is affected by estrogen depletion.(a,b) Expression of mRNAs encoding CHSTs (C4st1, C4st2, C6st1, or Galnac4s6st in a), and ChGns (Csgalnact1 or Csgalnact2 in b) in BMSCs isolated from 14-week-old WT female mice that were sham-operated (Sham) or ovariectomized (OVX) at 8 weeks of age. (n = 3 cultures, each from an independent mouse). Data are represented as mean ± s.d. *, P < 0.05. (c) μCT analysis of tibias of mice in a (n = 3 mice per group). BMD, bone mineral density. Data are represented as mean ± s.d. ***, P < 0.001.

Mentions: To evaluate in vivo effects of estrogens on CS-E production in bone-anabolic milieus, female mice were ovariextomized (OVX) to deplete endogenous estrogens. At 6 weeks after ovariectomy, BMSCs were isolated from femora of either OVX or sham-operated mice, and CS production in the isolated BMSCs was measured. Compared to cells isolated from sham-operated controls (Sham), BMSCs derived from OVX mice exhibited approximately a 50% reduction in CS level and a prominent decrease in the amount of E units (Table 2). Consistent with this observation, levels of C4st1 and Galnac4s6st, genes encoding E-unit-synthesizing enzymes, were significantly lower in BMSCs from OVX mice than those from Sham mice (Fig. 2a). In contrast, ovariectomy did not affect expression of Csgalnact1 or Csgalnact2 (Fig. 2b); these findings were reminiscent of those from estradiol-treated MC3T3-E1 cultures (Fig. 1b,c and Supplementary Fig. S1). Additionally, microcomputed tomography (μCT) analysis of tibias, which were excised from respective mice in the same time window as BMSC isolation, was performed to confirm that OVX mice exhibited characteristics of mouse-modeled postmenopausal osteoporosis. Indeed, OVX mice had significantly lower bone mineral density (BMD) in both cortical and trabecular bones than did control mice (Fig. 2c). These findings indicated that CS-E production in bone-forming cells was strictly regulated by estrogens in vivo.


Chondroitin sulfate-E mediates estrogen-induced osteoanabolism.

Koike T, Mikami T, Shida M, Habuchi O, Kitagawa H - Sci Rep (2015)

Biosynthetic machinery for CS-E production is affected by estrogen depletion.(a,b) Expression of mRNAs encoding CHSTs (C4st1, C4st2, C6st1, or Galnac4s6st in a), and ChGns (Csgalnact1 or Csgalnact2 in b) in BMSCs isolated from 14-week-old WT female mice that were sham-operated (Sham) or ovariectomized (OVX) at 8 weeks of age. (n = 3 cultures, each from an independent mouse). Data are represented as mean ± s.d. *, P < 0.05. (c) μCT analysis of tibias of mice in a (n = 3 mice per group). BMD, bone mineral density. Data are represented as mean ± s.d. ***, P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355730&req=5

f2: Biosynthetic machinery for CS-E production is affected by estrogen depletion.(a,b) Expression of mRNAs encoding CHSTs (C4st1, C4st2, C6st1, or Galnac4s6st in a), and ChGns (Csgalnact1 or Csgalnact2 in b) in BMSCs isolated from 14-week-old WT female mice that were sham-operated (Sham) or ovariectomized (OVX) at 8 weeks of age. (n = 3 cultures, each from an independent mouse). Data are represented as mean ± s.d. *, P < 0.05. (c) μCT analysis of tibias of mice in a (n = 3 mice per group). BMD, bone mineral density. Data are represented as mean ± s.d. ***, P < 0.001.
Mentions: To evaluate in vivo effects of estrogens on CS-E production in bone-anabolic milieus, female mice were ovariextomized (OVX) to deplete endogenous estrogens. At 6 weeks after ovariectomy, BMSCs were isolated from femora of either OVX or sham-operated mice, and CS production in the isolated BMSCs was measured. Compared to cells isolated from sham-operated controls (Sham), BMSCs derived from OVX mice exhibited approximately a 50% reduction in CS level and a prominent decrease in the amount of E units (Table 2). Consistent with this observation, levels of C4st1 and Galnac4s6st, genes encoding E-unit-synthesizing enzymes, were significantly lower in BMSCs from OVX mice than those from Sham mice (Fig. 2a). In contrast, ovariectomy did not affect expression of Csgalnact1 or Csgalnact2 (Fig. 2b); these findings were reminiscent of those from estradiol-treated MC3T3-E1 cultures (Fig. 1b,c and Supplementary Fig. S1). Additionally, microcomputed tomography (μCT) analysis of tibias, which were excised from respective mice in the same time window as BMSC isolation, was performed to confirm that OVX mice exhibited characteristics of mouse-modeled postmenopausal osteoporosis. Indeed, OVX mice had significantly lower bone mineral density (BMD) in both cortical and trabecular bones than did control mice (Fig. 2c). These findings indicated that CS-E production in bone-forming cells was strictly regulated by estrogens in vivo.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan.

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.

No MeSH data available.


Related in: MedlinePlus