PDF(Pubmed)
Abstract：
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.
摘要：
雌激素激动剂雷洛昔芬是FDA批准的绝经后妇女骨质疏松症的治疗，这也可能是一个有希望的预防疼痛椎间盘（IVD）退变。这里,我们假设:1)衰老和生物性别通过减少雌激素信号导致IVD变性;2)雷洛昔芬刺激雌激素信号以防止小鼠年龄和性别相关的IVD变性.将2.5月龄(雄性和雌性)和22.5月龄(雌性)C57Bl/6J小鼠皮下注射盐酸雷洛昔芬5x/周,持续6周(n=7-9/grp)。接下来,雌性小鼠在4月龄时进行卵巢切除(OVX)或假手术,并在6月龄时收获组织(n=5-6/grp).晚期老化和OVX增加IVD变性评分，IVD强度减弱，雌激素受体-α（ER-α）蛋白表达降低，神经递质P物质(SP)表达增加。与衰老相似，与男性IVD相比，女性IVD更退化，机械粘弹性较低，表达较少的ER-α蛋白，但与衰老或OVX引起的效应不同，女性的IVD机械力大于男性。治疗学上,全身注射雷洛昔芬促进ER-α蛋白通过增加IVD高度来平息这些失调，缓解IVD变性评分，增加IVD的强度和粘弹性，并降低年轻成年和老年雌性小鼠中SP的IVD细胞表达。转录，雷洛昔芬的注射上调ER-α的基因表达和细胞外基质相关的合成代谢在年轻成人和老年IVD。在椎骨中，晚期老化和OVX降低小梁BV/TV，而雷洛昔芬的注射增加了年轻成年和老年雌性小鼠的小梁BV/TV，但在年轻的成年雄性小鼠中却没有。在椎骨中，晚期衰老，OVX,和生物性别（女性>男性）增加了SP表达的骨细胞数量，而注射雷洛昔芬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。总的来说,在小鼠体内注射雌激素激动剂雷洛昔芬使IVD结构失调正常化，IVD力学，衰老和生物学性别诱导的IVD细胞和骨细胞中疼痛相关SP的表达。这些数据表明,除了骨质流失,雷洛昔芬可以缓解绝经后妇女因高龄引起的疼痛性IVD变性，生物性别，和雌激素消耗。
