Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats

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• 作者：Mirja Nurmio^a ; ^c ; ^{Mirja.Nurmio@utu.fi"" rel=""nofollow} ; Henna Joki^b ; ^{Henna.Joki@utu.fi"" rel=""nofollow} ; Jenny Kallio^a ; ^{Jenny.Kallio@utu.fi"" rel=""nofollow} ; Jorma A. Mä ; ä ; ttä ; ^b ; ^d ; ^{jorma.maatta@utu.fi"" rel=""nofollow} ; H. Kalervo Vä ; ä ; nä ; nen^b ; ^{kalervo.vaananen@utu.fi"" rel=""nofollow} ; Jorma Toppari^a ; ^c ; ^{Jorma.Toppari@utu.fi"" rel=""nofollow} ; Kirsi Jahnukainen^e ; ^f ; ^{Kirsi.Jahnukainen@utu.fi"" rel=""nofollow} ; Tiina Laitala-Leinonen^b ; ^{tilale@utu.fi"" rel=""nofollow}
• 关键词：Receptor tyrosine kinase ; Imatinib ; Bone resorption ; Osteoclast ; Osteoblast
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2011
• 出版时间：1 August 2011
• 年：2011
• 卷：254
• 期：3
• 页码：267-279
• 全文大小：2450 K

文摘

During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec®). Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5–7, or 100 mg/kg on postnatal days 5–13), and the effects of RTK inhibition on bone physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss.