Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway. Osteoarthritis Cartilage 2014 Sep;22(9):1327-36
Date
07/22/2014Pubmed ID
25042551Pubmed Central ID
PMC5452978DOI
10.1016/j.joca.2014.07.009Scopus ID
2-s2.0-85027958792 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
OBJECTIVE: Bisphosphonates are commonly used anti-osteoporotic drugs which have controversial effects on joint diseases including osteoarthritis. Certain bisphosphonates have been shown to have anabolic effects on cartilage which could have important ramifications for their proposed effects in vivo; however, the underlying mechanisms are poorly understood. Thus, the purpose of this study was to characterize the effects of clodronate on primary articular chondrocyte metabolism and to determine the underlying signaling pathways responsible.
DESIGN: The effects of clodronate and pamidronate on extracellular matrix (ECM) biosynthesis, accumulation and MMP-13 activity were observed in high density, 3D cultures of bovine articular chondrocytes for up to 4 weeks were evaluated. Mechanisms were delineated by measuring intracellular Ca(2+) signaling and the effects of pharmacologic inhibition of the purinergic receptor pathway.
RESULTS: Clodronate (100 μM) induced an anabolic effect (increased biosynthesis by 13-14%) which resulted in an 89-90% increase in ECM accumulation after 4 weeks of culture and without an associated effect on matrix turn-over. Stimulation by clodronate resulted in a 3.3-fold increase in Ca(2+) signaling and pharmacological inhibitor experiments suggested that the anabolic effects exerted by clodronate are transduced through the purinergic receptor pathway.
CONCLUSIONS: These findings support the previous notion that certain bisphosphonates may be useful as adjunctive therapies to potentially ameliorate progression of cartilage degeneration and improve arthritis management.
Author List
Rosa RG, Collavino K, Lakhani A, Delve E, Weber JF, Rosenthal AK, Waldman SDAuthor
Ann K. Rosenthal MD Associate Dean, Chief, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Anabolic AgentsAnimals
Bone Density Conservation Agents
Calcium Signaling
Cartilage, Articular
Cattle
Cells, Cultured
Chondrocytes
Clodronic Acid
Diphosphonates
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Extracellular Matrix
Matrix Metalloproteinase 13
Receptors, Purinergic
Signal Transduction