Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice.
Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice.
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DOI：
10.1530/joe-18-0153
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发表时间：
2018-07
期刊：
影响因子：
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通讯作者：
Ohlsson C
中科院分区：
文献类型：
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作者：
Funck-Brentano T;Nilsson KH;Brommage R;Henning P;Lerner UH;Koskela A;Tuukkanen J;Cohen-Solal M;Movérare-Skrtic S;Ohlsson C
WNT信号参与多种癌症的肿瘤发生并调节骨稳态。豪猪对WNT的棕榈酰化是WNT活性所必需的。豪猪抑制剂正在开发用于癌症治疗。由于豪猪抑制剂对骨骼健康可能产生的副作用尚不清楚，我们确定了它们对骨量和强度的影响。12周龄C57BL/6N雌性小鼠分别给予豪猪抑制剂LGK974（低剂量= 3 mg/kg/day，高剂量= 6 mg/kg/day）、Wnt-C59 （10 mg/kg/day）或对照药治疗3周。采用血清生物标志物、双能x线吸收仪、微CT和组织形态测定法评估骨参数。采用三点弯曲试验测定骨强度。正常体重证明豪猪抑制剂耐受性良好。与载药组相比，LGK974和Wnt-C59两种剂量均降低了全身骨密度（P < 0.001）。LGK974或Wnt-C59治疗后，股骨骨干皮质厚度（P < 0.001）和椎体小梁骨体积分数（P < 0.001）均降低。豪猪抑制降低了胫骨骨强度（P < 0.05）。皮质骨丢失是骨膜骨形成受损和皮质内骨吸收增加的结果，小梁骨丢失是小梁骨形成减少和骨吸收增加的结果。豪猪抑制剂由于骨形成减少和骨吸收增加而对骨量和强度产生有害影响。我们认为使用豪猪抑制剂的癌症靶向治疗可能会增加骨折的风险。
WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.