6′-Methoxy Raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding
6′-Methoxy Raloxifene-analog enhances mouse bone properties with reduced estrogen receptor binding
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6-甲氧基雷洛昔芬类似物通过减少雌激素受体结合增强小鼠骨特性
DOI：
10.1016/j.bonr.2020.100246
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发表时间：
2020
期刊：
影响因子：
2.5
通讯作者：
Wallace, Joseph M.
中科院分区：
文献类型：
--
作者：
Powell, Katherine M.;Brown, Alexa P.;Skaggs, Cayla G.;Pulliam, Alexis N.;Berman, Alycia G.;Deosthale, Padmini;Plotkin, Lilian I.;Allen, Matthew R.;Williams, David R.;Wallace, Joseph M.
雷洛昔芬（RAL）是FDA批准的用于治疗绝经后妇女骨质疏松症的药物。RAL主要通过其作为选择性雌激素受体调节剂（SERM）的作用抑制骨丢失。这种激素雌激素疗法促进了意想不到的副作用，如潮热和血栓形成风险增加，并防止药物用于一些有骨折风险的患者人群，包括患有骨骼疾病的儿童。最近已经证明，RAL可以通过与胶原蛋白结合并以非细胞依赖性方式增加骨组织水合作用，对整体骨机械性能产生显著的积极影响。通过用6-甲氧基取代6-羟基取代基来合成雷洛昔芬类似物（RAL-A），以降低化合物对雌激素受体（ER）的结合亲和力，同时保持其胶原蛋白结合能力。假设RAL-A将以类似于RAL的方式改善骨的机械完整性，但减少雌激素受体结合。分子评估显示，虽然RAL-A确实减少ER结合，但下游ER信号传导并未完全消除。在体外，RAL-A的表现与RAL相似，并且对骨细胞增殖、分化和功能具有相同的浓度阈值。为了评估体内治疗效果，用RAL或RAL-A对来自成骨不全（OI）鼠模型的野生型（WT）和杂合型（OIM+/−）雌性小鼠从8周龄至16周龄进行治疗。每个基因型也有一个未处理的对照组。使用microCT评估骨微结构，并使用3点弯曲评估力学行为。结果表明，两种化合物在胫骨骨小梁和皮质微结构中产生类似的增益。虽然WT的机械性能没有显著改变，但OIM+/−的机械性能显著增强，最明显的是屈服后性能，包括骨韧性。该概念验证研究显示出有希望的结果，并保证探索额外的类似物迭代，以进一步减少ER结合并提高抗断裂性。
Raloxifene (RAL) is an FDA-approved drug used to treat osteoporosis in postmenopausal women. RAL suppresses bone loss primarily through its role as a selective estrogen receptor modulator (SERM). This hormonal estrogen therapy promotes unintended side effects, such as hot flashes and increased thrombosis risk, and prevents the drug from being used in some patient populations at-risk for fracture, including children with bone disorders. It has recently been demonstrated that RAL can have significant positive effects on overall bone mechanical properties by binding to collagen and increasing bone tissue hydration in a cell-independent manner. A Raloxifene-Analog (RAL-A) was synthesized by replacing the 6-hydroxyl substituent with 6-methoxy in effort to reduce the compound's binding affinity for estrogen receptors (ER) while maintaining its collagen-binding ability. It was hypothesized that RAL-A would improve the mechanical integrity of bone in a manner similar to RAL, but with reduced estrogen receptor binding. Molecular assessment showed that while RAL-A did reduce ER binding, downstream ER signaling was not completely abolished.In-vitro, RAL-A performed similarly to RAL and had an identical concentration threshold on osteocyte cell proliferation, differentiation, and function. To assess treatment effectin-vivo, wildtype (WT) and heterozygous (OIM+/−) female mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL or RAL-A from 8 weeks to 16 weeks of age. There was an untreated control group for each genotype as well. Bone microarchitecture was assessed using microCT, and mechanical behavior was assessed using 3-point bending. Results indicate that both compounds produced analogous gains in tibial trabecular and cortical microarchitecture. While WT mechanical properties were not drastically altered with either treatment, OIM+/− mechanical properties were significantly enhanced, most notably, in post-yield properties including bone toughness. This proof-of-concept study shows promising results and warrants the exploration of additional analog iterations to further reduce ER binding and improve fracture resistance.
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成骨不全症：克隆具有移码突变的 pro-alpha 2(I) 胶原蛋白基因。
DOI：
--
发表时间：
1984
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Pihlajaniemi,T;Dickson,LA;Pope,FM;Korhonen,VR;Nicholls,A;Prockop,DJ;Myers,JC
通讯作者：
Myers,JC
影响因子：
4.1
作者：
Gourion-Arsiquaud, Samuel;Allen, Matthew R.;Burr, David B.;Vashishth, Deepak;Tang, Simon Y.;Boskey, Adele L.
通讯作者：
Boskey, Adele L.
影响因子：
4.1
作者：
Sims, NA;Dupont, S;Baron, R
通讯作者：
Baron, R
DOI：
--
发表时间：
--
期刊：
--
影响因子：
--
作者：
K. Livak;Thomas D. Schmittgen
通讯作者：
K. Livak;Thomas D. Schmittgen
影响因子：
4.1
作者：
van der Meulen, MCH;Jepsen, KJ;Mikic, B
通讯作者：
Mikic, B