Metastatic prostate cancer in the bone induces bone-forming lesions that contribute to progression and therapy resistance. Prostate cancer–induced bone formation originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Current strategies targeting prostate cancer–induced bone formation are lacking. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces prostate cancer–induced bone formation. Treatment with palovarotene, an RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro and decreased tumor-induced bone formation and tumor growth in several osteogenic prostate cancer models, and similar effects were observed with the pan-RAR agonist all-trans-retinoic acid (ATRA). Knockdown of RARα, β, or γ isoforms in ECs blocked BMP4-induced EC-to-OSB transition and osteoblast mineralization, indicating a role for all three isoforms in prostate cancer–induced bone formation. Furthermore, treatment with palovarotene or ATRA reduced plasma Tenascin C, a factor secreted from EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 formed a complex with RAR in the nucleus of ECs to activate EC-to-OSB transition. RAR activation by palovarotene or ATRA caused pSmad1 degradation by recruiting the E3-ubiquitin ligase Smad ubiquitination regulatory factor1 (Smurf1) to the nuclear pSmad1/RARγ complex, thus blocking EC-to-OSB transition. Collectively, these findings suggest that palovarotene can be repurposed to target prostate cancer–induced bone formation to improve clinical outcomes for patients with bone metastasis. Significance: This study provides mechanistic insights into how RAR agonists suppress prostate cancer–induced bone formation and offers a rationale for developing RAR agonists for prostate cancer bone metastasis therapy. See related commentary by Bhowmick and Bhowmick, p. 2975

中文翻译：

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视黄酸受体激活通过阻断内皮细胞向成骨细胞的转变减少转移性前列腺癌骨病变

骨中的转移性前列腺癌会诱发骨形成病变，从而导致进展和治疗抵抗。前列腺癌诱导的骨形成源自内皮细胞 (EC)，内皮细胞响应肿瘤分泌的 BMP4 而经历了内皮细胞向成骨细胞 (EC-to-OSB) 的转变。目前缺乏针对前列腺癌诱导的骨形成的策略。在这里，我们发现视黄酸受体 (RAR) 的激活会抑制 EC 向 OSB 的转变，并减少前列腺癌诱导的骨形成。palovarotene 是一种 RARγ 激动剂，正在测试进行性骨化性纤维发育不良的异位骨化，在体外抑制 EC 到 OSB 的转变和成骨细胞矿化，并在几种成骨性前列腺癌模型中减少肿瘤诱导的骨形成和肿瘤生长，泛 RAR 激动剂全反式视黄酸 (ATRA) 也观察到类似的效果。EC 中 RARα、β 或 γ 同工型的敲低可阻断 BMP4 诱导的 EC 至 OSB 的转变和成骨细胞矿化，表明所有三种同工型在前列腺癌诱导的骨形成中均发挥作用。此外，palovarotene 或 ATRA 治疗可降低血浆腱蛋白 C（一种 EC-OSB 细胞分泌的因子），可用于监测治疗反应。从机制上讲，BMP4 激活的 pSmad1 与 EC 细胞核中的 RAR 形成复合物，从而激活 EC 向 OSB 的转变。palovarotene 或 ATRA 激活 RAR，通过将 E3-泛素连接酶 Smad 泛素化调节因子 1 (Smurf1) 招募到核 pSmad1/RARγ 复合物，引起 pSmad1 降解，从而阻止 EC 向 OSB 的转变。总的来说，这些发现表明，palovarotene 可以重新用于靶向前列腺癌诱导的骨形成，以改善骨转移患者的临床结果。意义：这项研究提供了 RAR 激动剂如何抑制前列腺癌诱导的骨形成的机制见解，并为开发 RAR 激动剂用于前列腺癌骨转移治疗提供了理论基础。参见 Bhowmick 和 Bhowmick 的相关评论，第 17 页。2975