Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats
- Department of Physiology, University of Turku (Finland)
- Department of Cell Biology and Anatomy, University of Turku (Finland)
- Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institutet and University Hospital, Stockholm (Sweden)
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 (registered)) . 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. - Research Highlights: > 3-Day imatinib treatment. > Causes growth plate anomalies in young rats. > Causes biomechanical changes and significant bone loss at distal trabecular bone. > Results in loss of osteoclasts at osteochondral junction.
- OSTI ID:
- 21587803
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 254; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
AMINO ACIDS
ANIMAL CELLS
ANIMAL TISSUES
ANIMALS
BODY
BONE TISSUES
CARBOXYLIC ACIDS
COMPUTERIZED TOMOGRAPHY
CONNECTIVE TISSUE
CONNECTIVE TISSUE CELLS
DIAGNOSTIC TECHNIQUES
ELECTROMAGNETIC RADIATION
GROWTH
HYDROXY ACIDS
IN VIVO
INHIBITION
IONIZING RADIATIONS
MAMMALS
MEMBRANE PROTEINS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PHYSIOLOGY
PROTEINS
RADIATIONS
RATS
RECEPTORS
RNA
RODENTS
SIMULATION
SKELETON
SOMATIC CELLS
TOMOGRAPHY
TRABECULAR BONE
TYROSINE
VERTEBRATES
X RADIATION