title: Inhibition of T-Type Voltage Sensitive Calcium Channel Reduces Load-Induced OA in Mice and Suppresses the Catabolic Effect of Bone Mechanical Stress on Chondrocytes.
abstract: Voltage-sensitive calcium channels (VSCC) regulate cellular calcium influx, one of the earliest responses to mechanical stimulation in osteoblasts. Here, we postulate that T-type VSCCs play an essential role in bone mechanical response to load and participate in events leading to the pathology of load-induced OA. Repetitive mechanical insult was used to induce OA in Cav3.2 T-VSCC null and wild-type control mouse knees. Osteoblasts (MC3T3-E1) and chondrocytes were treated with a selective T-VSCC inhibitor and subjected to fluid shear stress to determine how blocking of T-VSCCs alters the expression profile of each cell type upon mechanical stimulation. Conditioned-media (CM) obtained from static and sheared MC3T3-E1 was used to assess the effect of osteoblast-derived factors on the chondrocyte phenotype. T-VSCC null knees exhibited significantly lower focal articular cartilage damage than age-matched controls. In vitro inhibition of T-VSCC significantly reduced the expression of both early and late mechanoresponsive genes in osteoblasts but had no effect on gene expression in chondrocytes. Furthermore, treatment of chondrocytes with CM obtained from sheared osteoblasts induced expression of markers of hypertrophy in chondrocytes and this was nearly abolished when osteoblasts were pre-treated with the T-VSCC-specific inhibitor. These results indicate that T-VSCC plays a role in signaling events associated with induction of OA and is essential to the release of osteoblast-derived factors that promote an early OA phenotype in chondrocytes. Further, these findings suggest that local inhibition of T-VSCC may serve as a therapy for blocking load-induced bone formation that results in cartilage degeneration.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, Delaware, 19716, United States of America.
authors.forename: Padma P
authors.initials: PP
authors.lastname: Srinivasan
authors.affiliation: Biomedical Engineering Program, University of Delaware, Newark, Delaware, 19716, United States of America.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Parajuli
authors.affiliation: Biomedical Engineering Program, University of Delaware, Newark, Delaware, 19716, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Price
authors.affiliation: Department of Mechanical Engineering, University of Delaware, Newark, Delaware, 19716, United States of America.
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, Delaware, 19716, United States of America; Biomedical Engineering Program, University of Delaware, Newark, Delaware, 19716, United States of America; Department of Mechanical Engineering, University of Delaware, Newark, Delaware, 19716, United States of America.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Duncan
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, Delaware, 19716, United States of America; Biomedical Engineering Program, University of Delaware, Newark, Delaware, 19716, United States of America.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Kirn-Safran
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism / Q000502:physiology; D019902:Chondrocytes / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D008660:Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: D020747:Calcium Channels, T-Type