A hyaluronic acid-salmon calcitonin conjugate for the local treatment of osteoarthritis: chondro-protective effect in a rabbit model of early OA.
Osteoarthritis (OA) is characterized by chronic degeneration of joints, involving mainly the articular cartilage and the underlying bone, and severely impairing the quality of life of the patient. Although with limited efficacy, currently available pharmacological treatments for OA aim to control pain and to retard disease progression. Salmon calcitonin (sCT) is a drug which has been shown to have therapeutic effects in experimental arthritis by inhibiting both bone turnover and cartilage degradation and reducing the activities of matrix metalloproteinases (MMP). High molecular weight hyaluronic acid (HA) is used as a lubricant in OA therapy, and, interestingly, HA polymers may normalize the levels of MMP-1, -3 and -13. We demonstrated that sCT rapidly clears from the knee joint of rat animal model, after intra-articular (i.a.) administration, and it induces systemic effects. Here, sCT was conjugated to HA (200kDa) with the aim of prolonging the residence time of the polypeptide in the joint space by reducing its clearance. An aldehyde derivative of HA was used for N-terminal site-selective coupling of sCT. The activity of sCT was preserved, both in vitro and in vivo, after its conjugation and the i.a. injection of HA-sCT did not trigger any systemic effects in rats. The efficacy of HA-sCT treatment was tested in a rabbit OA model and clear chondro-protective effect was proven by macro- and microscopic assessments and histological findings. Our results indicate that HAylation of sCT increases the size of the polypeptide in a stable covalent manner and delays its passage into the blood stream. We conclude that HA conjugation prolongs the anti-catabolic effects of sCT in joint tissues, including the synovial membrane and cartilage.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy.
Anna
A
Mero
Fidia Farmaceutici, Via Ponte della Fabbrica 3/A, 35031 Abano Terme, Italy.
Monica
M
Campisi
Rheumatology Unit, University Hospital of Padova, Via Giustiniani 2, 35128, Padova, Italy.
Marta
M
Favero
Fidia Farmaceutici, Via Ponte della Fabbrica 3/A, 35031 Abano Terme, Italy.
Carlo
C
Barbera
Fidia Farmaceutici, Via Ponte della Fabbrica 3/A, 35031 Abano Terme, Italy.
Cynthia
C
Secchieri
Faculty of Medicine, CMU, 1, rue Michel-Servet, CH-1211 Geneva, Switzerland.
Jean M
JM
Dayer
Hospital for Special Surgery, 535 East 70th Street, New York, 10021, USA; Laboratory for Cartilage Biology, Hospital for Special Surgery, Weill Cornell Medical College, New York, USA.
Mary B
MB
Goldring
Hospital for Special Surgery, 535 East 70th Street, New York, 10021, USA.
Steven R
SR
Goldring
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy. Electronic address: gianfranco.pasut@unipd.it.
Gianfranco
G
Pasut
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D002116:Calcitonin / Q000008:administration & dosage* / Q000737:chemistry; D002118:Calcium / Q000097:blood; D002358:Cartilage, Articular / Q000473:pathology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D007719:Knee Joint / Q000378:metabolism; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy*; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D013552:Swine
D000893:Anti-Inflammatory Agents; C028815:salmon calcitonin; D006820:Hyaluronic Acid; D002116:Calcitonin; D000242:Cyclic AMP; D002118:Calcium
Arthritis; Hyaluronic acid; Polymer conjugation; Salmon calcitonin