Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate
Objective: Insulin-like growth factor 1 (IGF-1) stimulates cartilage repair but is not a practical therapy due to its short half-life. We have previously modified IGF-1 by adding a heparin-binding domain and have shown that this fusion protein (HB-IGF-1) stimulates sustained proteoglycan synthesis...
| Main Authors: | , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Wiley Blackwell
2013
|
| Online Access: | http://hdl.handle.net/1721.1/76249 https://orcid.org/0000-0002-8911-7998 https://orcid.org/0000-0002-4942-3456 |
| _version_ | 1826191750504382464 |
|---|---|
| author | Miller, Rachel Elizabeth Grodzinsky, Alan J. Cummings, Kiersten Plaas, Anna H. K. Cole, Ada A. Lee, Richard T. Patwari, Parth |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Miller, Rachel Elizabeth Grodzinsky, Alan J. Cummings, Kiersten Plaas, Anna H. K. Cole, Ada A. Lee, Richard T. Patwari, Parth |
| author_sort | Miller, Rachel Elizabeth |
| collection | MIT |
| description | Objective:
Insulin-like growth factor 1 (IGF-1) stimulates cartilage repair but is not a practical therapy due to its short half-life. We have previously modified IGF-1 by adding a heparin-binding domain and have shown that this fusion protein (HB-IGF-1) stimulates sustained proteoglycan synthesis in cartilage. This study was undertaken to examine the mechanism by which HB-IGF-1 is retained in cartilage and to test whether HB-IGF-1 provides sustained growth factor delivery to cartilage in vivo and to human cartilage explants.
Methods:
Retention of HB-IGF-1 and IGF-1 was analyzed by Western blotting. The necessity of heparan sulfate (HS) or chondroitin sulfate (CS) glycosaminoglycans (GAGs) for binding was tested using enzymatic removal and cells with genetic deficiency of HS. Binding affinities of HB-IGF-1 and IGF-1 proteins for isolated GAGs were examined by surface plasmon resonance and enzyme-linked immunosorbent assay.
Results:
In cartilage explants, chondroitinase treatment decreased binding of HB-IGF-1, whereas heparitinase had no effect. Furthermore, HS was not necessary for HB-IGF-1 retention on cell monolayers. Binding assays showed that HB-IGF-1 bound both CS and HS, whereas IGF-1 did not bind either. After intraarticular injection in rat knees, HB-IGF-1 was retained in articular and meniscal cartilage, but not in tendon, consistent with enhanced delivery to CS-rich cartilage. Finally, HB-IGF-1 was retained in human cartilage explants but IGF-1 was not.
Conclusion:
Our findings indicate that after intraarticular injection in rats, HB-IGF-1 is specifically retained in cartilage through its high abundance of CS. Modification of growth factors with heparin-binding domains may be a new strategy for sustained and specific local delivery to cartilage. |
| first_indexed | 2024-09-23T09:00:43Z |
| format | Article |
| id | mit-1721.1/76249 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:00:43Z |
| publishDate | 2013 |
| publisher | Wiley Blackwell |
| record_format | dspace |
| spelling | mit-1721.1/762492022-09-26T09:47:49Z Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate Miller, Rachel Elizabeth Grodzinsky, Alan J. Cummings, Kiersten Plaas, Anna H. K. Cole, Ada A. Lee, Richard T. Patwari, Parth Massachusetts Institute of Technology. Department of Biological Engineering Miller, Rachel Elizabeth Grodzinsky, Alan J. Objective: Insulin-like growth factor 1 (IGF-1) stimulates cartilage repair but is not a practical therapy due to its short half-life. We have previously modified IGF-1 by adding a heparin-binding domain and have shown that this fusion protein (HB-IGF-1) stimulates sustained proteoglycan synthesis in cartilage. This study was undertaken to examine the mechanism by which HB-IGF-1 is retained in cartilage and to test whether HB-IGF-1 provides sustained growth factor delivery to cartilage in vivo and to human cartilage explants. Methods: Retention of HB-IGF-1 and IGF-1 was analyzed by Western blotting. The necessity of heparan sulfate (HS) or chondroitin sulfate (CS) glycosaminoglycans (GAGs) for binding was tested using enzymatic removal and cells with genetic deficiency of HS. Binding affinities of HB-IGF-1 and IGF-1 proteins for isolated GAGs were examined by surface plasmon resonance and enzyme-linked immunosorbent assay. Results: In cartilage explants, chondroitinase treatment decreased binding of HB-IGF-1, whereas heparitinase had no effect. Furthermore, HS was not necessary for HB-IGF-1 retention on cell monolayers. Binding assays showed that HB-IGF-1 bound both CS and HS, whereas IGF-1 did not bind either. After intraarticular injection in rat knees, HB-IGF-1 was retained in articular and meniscal cartilage, but not in tendon, consistent with enhanced delivery to CS-rich cartilage. Finally, HB-IGF-1 was retained in human cartilage explants but IGF-1 was not. Conclusion: Our findings indicate that after intraarticular injection in rats, HB-IGF-1 is specifically retained in cartilage through its high abundance of CS. Modification of growth factors with heparin-binding domains may be a new strategy for sustained and specific local delivery to cartilage. National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant EB-003805) National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (Grant AR-045779) 2013-01-10T21:20:10Z 2013-01-10T21:20:10Z 2010-11 2010-04 Article http://purl.org/eprint/type/JournalArticle 0004-3591 1529-0131 http://hdl.handle.net/1721.1/76249 Miller, Rachel E. et al. “Intraarticular Injection of Heparin-binding Insulin-like Growth Factor 1 Sustains Delivery of Insulin-like Growth Factor 1 to Cartilage Through Binding to Chondroitin Sulfate.” Arthritis & Rheumatism 62.12 (2010): 3686–3694. https://orcid.org/0000-0002-8911-7998 https://orcid.org/0000-0002-4942-3456 en_US http://dx.doi.org/10.1002/art.27709 Arthritis and Rheumatism Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Wiley Blackwell PMC |
| spellingShingle | Miller, Rachel Elizabeth Grodzinsky, Alan J. Cummings, Kiersten Plaas, Anna H. K. Cole, Ada A. Lee, Richard T. Patwari, Parth Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate |
| title | Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate |
| title_full | Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate |
| title_fullStr | Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate |
| title_full_unstemmed | Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate |
| title_short | Intra-articular Injection of HB-IGF-1 Sustains Delivery of IGF-1 to Cartilage through Binding to Chondroitin Sulfate |
| title_sort | intra articular injection of hb igf 1 sustains delivery of igf 1 to cartilage through binding to chondroitin sulfate |
| url | http://hdl.handle.net/1721.1/76249 https://orcid.org/0000-0002-8911-7998 https://orcid.org/0000-0002-4942-3456 |
| work_keys_str_mv | AT millerrachelelizabeth intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate AT grodzinskyalanj intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate AT cummingskiersten intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate AT plaasannahk intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate AT coleadaa intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate AT leerichardt intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate AT patwariparth intraarticularinjectionofhbigf1sustainsdeliveryofigf1tocartilagethroughbindingtochondroitinsulfate |