Raloxifene Stimulates Estrogen Signaling to Protect Against Age- and Sex-Related Intervertebral Disc Degeneration in Mice.
Raloxifene Stimulates Estrogen Signaling to Protect Against Age- and Sex-Related Intervertebral Disc Degeneration in Mice.
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DOI：
10.3389/fbioe.2022.924918
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发表时间：
2022
影响因子：
5.7
通讯作者：
Holguin, Nilsson
中科院分区：
文献类型：
--
作者：
Bhadouria, Neharika;Berman, Alycia G.;Wallace, Joseph M.;Holguin, Nilsson
雌激素激动剂雷洛昔芬是 FDA 批准的一种治疗绝经后妇女骨质疏松症的药物，也可能是一种有前景的疼痛性椎间盘 (IVD) 退变的预防药物。在这里，我们假设 1) 衰老和生物性别通过减少雌激素信号传导导致 IVD 变性，2) 雷洛昔芬刺激雌激素信号传导，以防止小鼠体内与年龄和性别相关的 IVD 变性。 2.5 个月大（雄性和雌性）和 22.5 个月大（雌性）C57Bl/6J 小鼠皮下注射盐酸雷洛昔芬 5 次/周，持续 6 周（n = 7-9/组）。接下来，雌性小鼠在 4 个月大时进行卵巢切除 (OVX) 或假手术，并在 6 个月时收获组织 (n = 5-6/grp)。晚期衰老和OVX增加了IVD退化评分，减弱了IVD强度，减少了雌激素受体-α（ER-α）蛋白表达，并增加了神经递质P物质（SP）表达。与衰老相似，与男性 IVD 相比，女性 IVD 退化程度更高，机械粘弹性更小，ER-α 蛋白表达更少，但与衰老或 OVX 引起的效应不同，女性 IVD 机械力大于男性。在治疗上，全身注射雷洛昔芬可促进 ER-α 蛋白通过增大 IVD 高度、减轻 IVD 变性评分、增加 IVD 的强度和粘弹性以及减少年轻成年和老年雌性小鼠 IVD 细胞 SP 的表达来平息这些失调。在转录方面，注射雷洛昔芬上调了年轻成人和老年 IVD 中 ER-α 的基因表达和细胞外基质相关的合成代谢。在椎骨中，晚期衰老和 OVX 降低了年轻成年和老年雌性小鼠的小梁 BV/TV，而注射雷洛昔芬则增加了年轻成年雄性小鼠的小梁 BV/TV，但不会增加年轻成年雄性小鼠的骨小梁 BV/TV。在椎骨中，晚期衰老、OVX和生物性别（雌性>雄性）增加了表达SP的骨细胞数量，而注射雷洛昔芬则减少了年轻成年雌性和雄性小鼠以及老年雌性小鼠中表达SP的骨细胞数量。总体而言，向小鼠注射雌激素激动剂雷洛昔芬可以使衰老和生物性别引起的 IVD 细胞和骨细胞中 IVD 结构、IVD 力学以及疼痛相关 SP 表达的失调正常化。这些数据表明，除了骨质流失之外，雷洛昔芬还可以缓解绝经后妇女因高龄、生物性别和雌激素耗竭而引起的痛苦的 IVD 退化。
Estrogen agonist raloxifene is an FDA-approved treatment of osteoporosis in postmenopausal women, which may also be a promising prophylactic for painful intervertebral disc (IVD) degeneration. Here, we hypothesized that 1) aging and biological sex contribute to IVD degeneration by reducing estrogen signaling and that 2) raloxifene stimulates estrogen signaling to protect against age- and sex-related IVD degeneration in mice. 2.5-month-old (male and female) and 22.5-month-old (female) C57Bl/6J mice were subcutaneously injected with raloxifene hydrochloride 5x/week for 6 weeks (n = 7–9/grp). Next, female mice were ovariectomized (OVX) or sham operated at 4 months of age and tissues harvested at 6 months (n = 5–6/grp). Advanced aging and OVX increased IVD degeneration score, weakened IVD strength, reduced estrogen receptor-α (ER-α) protein expression, and increased neurotransmitter substance P (SP) expression. Similar to aging and compared with male IVDs, female IVDs were more degenerated, mechanically less viscoelastic, and expressed less ER-α protein, but unlike the effect induced by aging or OVX, IVD mechanical force was greater in females than in males. Therapeutically, systemic injection of raloxifene promoted ER-α protein to quell these dysregulations by enlarging IVD height, alleviating IVD degeneration score, increasing the strength and viscoelastic properties of the IVD, and reducing IVD cell expression of SP in young-adult and old female mice. Transcriptionally, injection of raloxifene upregulated the gene expression of ER-α and extracellular matrix-related anabolism in young-adult and old IVD. In vertebra, advanced aging and OVX reduced trabecular BV/TV, whereas injection of raloxifene increased trabecular BV/TV in young-adult and old female mice, but not in young-adult male mice. In vertebra, advanced aging, OVX, and biological sex (females > males) increased the number of SP-expressing osteocytes, whereas injection of raloxifene reduced the number of SP-expressing osteocytes in young-adult female and male mice and old female mice. Overall, injection of estrogen agonist raloxifene in mice normalized dysregulation of IVD structure, IVD mechanics, and pain-related SP expression in IVD cells and osteocytes induced by aging and biological sex. These data suggest that, in addition to bone loss, raloxifene may relieve painful IVD degeneration in postmenopausal women induced by advanced age, biological sex, and estrogen depletion.
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影响因子：
4.1
作者：
Gallant, Maxime A.;Brown, Drew M.;Hammond, Max;Wallace, Joseph M.;Du, Jiang;Deymier-Black, Alix C.;Almer, Jonathan D.;Stock, Stuart R.;Allen, Matthew R.;Burr, David B.
通讯作者：
Burr, David B.
影响因子：
3.3
作者：
Holguin, Nilsson;Uzer, Gunes;Judex, Stefan
通讯作者：
Judex, Stefan
影响因子：
168.9
作者：
Freemont, AJ;Peacock, TE;Jayson, MIV
通讯作者：
Jayson, MIV
影响因子：
6.9
作者：
Berman, Alycia G.;Wallace, Joseph M.;Allen, Matthew R.
通讯作者：
Allen, Matthew R.
影响因子：
6.1
作者：
Baron, YM;Brincat, MP;Calleja, N
通讯作者：
Calleja, N