Sclerostin-Neutralizing Antibody Treatment Rescues Negative Effects of Rosiglitazone on Mouse Bone Parameters.
Sclerostin-Neutralizing Antibody Treatment Rescues Negative Effects of Rosiglitazone on Mouse Bone Parameters.
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DOI：
10.1002/jbmr.4170
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Reagan MR
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文献类型：
--
作者：
Farrell M;Fairfield H;Costa S;D'Amico A;Falank C;Brooks DJ;Reagan MR
肥胖是一种日益严重的流行病，是许多癌症的危险因素，并导致骨髓脂肪组织（BMAT）增加。体外研究和肥胖动物模型表明，BMAT有助于癌症进展，但缺乏临床前模型来直接测试BMAT在癌症中的作用。过氧化物酶体增殖物激活受体-γ（过氧化物酶体增殖物激活受体-γ）的过度激活可使骨形成和骨吸收速率发生偏移，导致BMAT和小梁骨丢失增加。噻唑烷二酮类（例如，罗格列酮）是通过激活PPARγ促进脂肪生成的抗糖尿病疗法。我们研究了罗格列酮是否会增加癌症研究中常用的免疫功能低下模型中的BMAT，以及这些作用是否可以通过联合给予骨合成代谢剂（硬化蛋白中和抗体，SOST Ab）来逆转，该药物已被证明可以抑制脂肪生成，使用DEXA，μCT，OsO 4 μCT和动态组织形态计量学。罗格列酮在雌性SCID Beige小鼠（队列1）中给药4周后，通过增加破骨细胞和成骨细胞活性，显著降低了约一半的骨小梁体积（BV/TV），并显著增加了BMAT。在组群2中，向小鼠施用罗格列酮± SOST Ab 4周，然后停用罗格列酮并继续SOST Ab或媒介物6周。SOST Ab显著增加骨参数（例如，BV/TV、N. O B/B.Pm和MS/BS）。SOST Ab还克服了罗格列酮的许多负面影响（例如，对骨小梁参数的影响，MLT增加，BFR降低）。有趣的是，SOST Ab显著降低罗格列酮诱导的股骨BMAT，主要是由于脂肪细胞大小的减少，但对胫骨BMAT的影响要弱得多。这些数据表明，靶向sclerostin可以防止罗格列酮诱导的骨丢失，并减少BM肥胖，在一些，但不是所有的BMAT位置。总的来说，我们的数据表明罗格列酮增加了SCID Beige小鼠的BMAT，但骨的伴随变化可能会混淆其用于特异性确定BMAT在肿瘤模型中的作用。
Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). In vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT’s role in cancer. Over activation of PPARγ (peroxisome-proliferator-activated receptor-γ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (e.g., rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody, SOST Ab), which has been shown to inhibit adipogenesis, using DEXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± SOST Ab for 4 weeks, and then rosiglitazone was discontinued and SOST Ab or vehicle was continued for 6 weeks. SOST Ab significantly increased bone parameters (eg. BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. SOST Ab also overcame many negative effects of rosiglitazone (eg. effects on trabecular bone parameters, increased MLT, and decreased BFR). Interestingly, SOST Ab significantly decreased rosiglitazone induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT’s role in tumor models.
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