title: Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway.
abstract: 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.
  
  
  METHODS
  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.
authors.affiliation: Human Mobility Research Centre, Kingston General Hospital, Kingston, Ontario, Canada. Electronic address: renata.giardini@gmail.com.
authors.forename: R G
authors.initials: RG
authors.lastname: Rosa
authors.affiliation: Department of Chemical Engineering, Ryerson University, Toronto, Ontario, Canada; Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: kristina.collavino@ryerson.ca.
authors.forename: K
authors.initials: K
authors.lastname: Collavino
authors.affiliation: Department of Chemical Engineering, Queen's University, Kingston, Ontario, Canada. Electronic address: anand.lakhani@queensu.ca.
authors.forename: A
authors.initials: A
authors.lastname: Lakhani
authors.affiliation: Department of Chemical Engineering, Queen's University, Kingston, Ontario, Canada. Electronic address: elizabeth.delve@mail.utoronto.ca.
authors.forename: E
authors.initials: E
authors.lastname: Delve
authors.affiliation: Department of Mechanical & Materials Engineering, Queen's University, Kingston, Ontario, Canada. Electronic address: weberj@me.queensu.ca.
authors.forename: J F
authors.initials: JF
authors.lastname: Weber
authors.affiliation: Division of Rheumatology, Department of Medicine, Medical College of Wisconsin, and the Zablocki VA Medical Center, Milwaukee, WI, USA. Electronic address: ann.rosenthal@va.gov.
authors.forename: A K
authors.initials: AK
authors.lastname: Rosenthal
authors.affiliation: Department of Chemical Engineering, Ryerson University, Toronto, Ontario, Canada; Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: swaldman@ryerson.ca.
authors.forename: S D
authors.initials: SD
authors.lastname: Waldman
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D000077268:Pamidronate; D011983:Receptors, Purinergic / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D045930:Anabolic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D011983:Receptors, Purinergic; D004002:Clodronic Acid; D053509:Matrix Metalloproteinase 13; D000077268:Pamidronate
keywords: Anabolism; Bisphosphonates; Calcium signaling; Chondrocytes; Clodronate; Purinergic signaling