Bone growth during rapamycin therapy in young rats
<p>Abstract</p> <p>Background</p> <p>Rapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogeni...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2009-01-01
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| Series: | BMC Pediatrics |
| Online Access: | http://www.biomedcentral.com/1471-2431/9/3 |
| _version_ | 1819121484628492288 |
|---|---|
| author | He Yu-Zhu Sanchez Cheryl P |
| author_facet | He Yu-Zhu Sanchez Cheryl P |
| author_sort | He Yu-Zhu |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Rapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogenic properties.</p> <p>Methods</p> <p>Weanling three week old rats were given rapamycin at 2.5 mg/kg daily by gavage for 2 or 4 weeks and compared to a Control group given equivalent amount of saline. Morphometric measurements and biochemical determinations for serum calcium, phosphate, iPTH, urea nitrogen, creatinine and insulin-growth factor I (IGF-I) were obtained. Histomorphometric analysis of the growth plate cartilage, in-situ hybridization experiments and immunohistochemical studies for various proteins were performed to evaluate for chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption.</p> <p>Results</p> <p>At the end of the 2 weeks, body and tibia length measurements were shorter after rapamycin therapy associated with an enlargement of the hypertrophic zone in the growth plate cartilage. There was a decrease in chondrocyte proliferation assessed by <it>histone-4 </it>and <it>mammalian target of rapamycin </it>(<it>mTOR</it>) expression. A reduction in <it>parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) </it>and an increase in <it>Indian hedgehog </it>(<it>Ihh</it>) expression may explain in part, the increase number of hypertrophic chondrocytes. The number of TRAP positive multinucleated chondro/osteoclasts declined in the chondro-osseous junction with a decrease in the <it>receptor activator of nuclear factor kappa β ligand </it>(<it>RANKL</it>) and <it>vascular endothelial growth factor </it>(<it>VEGF</it>) expression. Although body and tibial length remained short after 4 weeks of rapamycin, changes in the expression of chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption which were significant after 2 weeks of rapamycin improved at the end of 4 weeks.</p> <p>Conclusion</p> <p>When given to young rats, 2 weeks of rapamycin significantly decreased endochondral bone growth. No catch-up growth was demonstrated at the end of 4 weeks, although markers of chondrocyte proliferation and differentiation improved. Clinical studies need to be done to evaluate these changes in growing children.</p> |
| first_indexed | 2024-12-22T06:37:18Z |
| format | Article |
| id | doaj.art-0d184d34f4234b5c8d11e931b7f550a2 |
| institution | Directory Open Access Journal |
| issn | 1471-2431 |
| language | English |
| last_indexed | 2024-12-22T06:37:18Z |
| publishDate | 2009-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Pediatrics |
| spelling | doaj.art-0d184d34f4234b5c8d11e931b7f550a22022-12-21T18:35:33ZengBMCBMC Pediatrics1471-24312009-01-0191310.1186/1471-2431-9-3Bone growth during rapamycin therapy in young ratsHe Yu-ZhuSanchez Cheryl P<p>Abstract</p> <p>Background</p> <p>Rapamycin is an effective immunosuppressant widely used to maintain the renal allograft in pediatric patients. Linear growth may be adversely affected in young children since rapamycin has potent anti-proliferative and anti-angiogenic properties.</p> <p>Methods</p> <p>Weanling three week old rats were given rapamycin at 2.5 mg/kg daily by gavage for 2 or 4 weeks and compared to a Control group given equivalent amount of saline. Morphometric measurements and biochemical determinations for serum calcium, phosphate, iPTH, urea nitrogen, creatinine and insulin-growth factor I (IGF-I) were obtained. Histomorphometric analysis of the growth plate cartilage, in-situ hybridization experiments and immunohistochemical studies for various proteins were performed to evaluate for chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption.</p> <p>Results</p> <p>At the end of the 2 weeks, body and tibia length measurements were shorter after rapamycin therapy associated with an enlargement of the hypertrophic zone in the growth plate cartilage. There was a decrease in chondrocyte proliferation assessed by <it>histone-4 </it>and <it>mammalian target of rapamycin </it>(<it>mTOR</it>) expression. A reduction in <it>parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) </it>and an increase in <it>Indian hedgehog </it>(<it>Ihh</it>) expression may explain in part, the increase number of hypertrophic chondrocytes. The number of TRAP positive multinucleated chondro/osteoclasts declined in the chondro-osseous junction with a decrease in the <it>receptor activator of nuclear factor kappa β ligand </it>(<it>RANKL</it>) and <it>vascular endothelial growth factor </it>(<it>VEGF</it>) expression. Although body and tibial length remained short after 4 weeks of rapamycin, changes in the expression of chondrocyte proliferation, chondrocyte differentiation and chondro/osteoclastic resorption which were significant after 2 weeks of rapamycin improved at the end of 4 weeks.</p> <p>Conclusion</p> <p>When given to young rats, 2 weeks of rapamycin significantly decreased endochondral bone growth. No catch-up growth was demonstrated at the end of 4 weeks, although markers of chondrocyte proliferation and differentiation improved. Clinical studies need to be done to evaluate these changes in growing children.</p>http://www.biomedcentral.com/1471-2431/9/3 |
| spellingShingle | He Yu-Zhu Sanchez Cheryl P Bone growth during rapamycin therapy in young rats BMC Pediatrics |
| title | Bone growth during rapamycin therapy in young rats |
| title_full | Bone growth during rapamycin therapy in young rats |
| title_fullStr | Bone growth during rapamycin therapy in young rats |
| title_full_unstemmed | Bone growth during rapamycin therapy in young rats |
| title_short | Bone growth during rapamycin therapy in young rats |
| title_sort | bone growth during rapamycin therapy in young rats |
| url | http://www.biomedcentral.com/1471-2431/9/3 |
| work_keys_str_mv | AT heyuzhu bonegrowthduringrapamycintherapyinyoungrats AT sanchezcherylp bonegrowthduringrapamycintherapyinyoungrats |