Jay Freya F, Vaidya Mithila, Porada Sabrina M, Andrukhova Olena, Schneider Marlon R, Erben Reinhold G
Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Germany.
Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
Mol Cell Endocrinol. 2015 Dec 5;417:158-65. doi: 10.1016/j.mce.2015.09.031. Epub 2015 Sep 30.
Although parathyroid hormone (PTH) has long been known to act as a bone anabolic agent when administered intermittently, the exact underlying mechanisms remain largely unknown. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, has been identified to be a PTH target gene in vitro and in vivo. Here, we used female global AREG knockout (AREG-KO) mice to explore the role of AREG in mediating the bone anabolic effects of PTH. AREG-KO mice were characterized by unchanged distal femoral cancellous bone mass and only subtle decreases in bone mineral density (BMD) and cortical thickness at the femoral midshaft at 3 and 8 months of age, relative to wildtype controls. AREG deficiency was associated with complex changes in the mRNA expression of other EGFR ligands in femoral cancellous bone osteoblasts in situ in 3-week-old mice. To examine the bone anabolic effects of PTH in the absence and presence of AREG, we injected 3-month-old AREG-KO females and wildtype control littermates with 80 μg/kg PTH or vehicle 5 times per week over 4 weeks. Intermittent PTH treatment of AREG-KO mice led to increases in femoral trabecular and cortical BMD, cortical thickness, endocortical and periosteal bone formation, cancellous bone formation rate, and serum osteocalcin, comparable to those observed in wildtype control mice. In conclusion, our data indicate that the bone anabolic effects of PTH do not require AREG, at least in 3-month-old female mice.
尽管长期以来人们都知道甲状旁腺激素（PTH）间歇性给药时可作为一种骨合成代谢剂，但其确切的潜在机制在很大程度上仍不清楚。双调蛋白（AREG）是表皮生长因子受体的一种配体，已被确定为体内外PTH的靶基因。在此，我们使用雌性AREG基因敲除（AREG-KO）小鼠来探究AREG在介导PTH的骨合成代谢作用中的作用。与野生型对照相比，AREG-KO小鼠在3个月和8个月大时，其股骨远端松质骨量未发生变化，仅股骨中轴处的骨矿物质密度（BMD）和皮质厚度略有降低。在3周龄小鼠的股骨松质骨成骨细胞中，AREG缺乏与其他表皮生长因子受体（EGFR）配体的mRNA表达的复杂变化有关。为了研究在有和没有AREG的情况下PTH的骨合成代谢作用，我们给3个月大的AREG-KO雌性小鼠和野生型对照同窝小鼠每周注射5次80 μg/kg的PTH或赋形剂，持续4周。间歇性PTH治疗AREG-KO小鼠导致股骨小梁和皮质BMD增加、皮质厚度增加、骨内膜和骨膜骨形成增加、松质骨形成率增加以及血清骨钙素增加，与野生型对照小鼠中观察到的情况相当。总之，我们的数据表明，至少在3个月大的雌性小鼠中，PTH的骨合成代谢作用不需要AREG。
