title: Autologous Bone Marrow-Derived Mesenchymal Stem Cells Modulate Molecular Markers of Inflammation in Dogs with Cruciate Ligament Rupture.
abstract: Mid-substance rupture of the canine cranial cruciate ligament rupture (CR) and associated stifle osteoarthritis (OA) is an important veterinary health problem. CR causes stifle joint instability and contralateral CR often develops. The dog is an important model for human anterior cruciate ligament (ACL) rupture, where rupture of graft repair or the contralateral ACL is also common. This suggests that both genetic and environmental factors may increase ligament rupture risk. We investigated use of bone marrow-derived mesenchymal stem cells (BM-MSCs) to reduce systemic and stifle joint inflammatory responses in dogs with CR. Twelve dogs with unilateral CR and contralateral stable partial CR were enrolled prospectively. BM-MSCs were collected during surgical treatment of the unstable CR stifle and culture-expanded. BM-MSCs were subsequently injected at a dose of 2x106 BM-MSCs/kg intravenously and 5x106 BM-MSCs by intra-articular injection of the partial CR stifle. Blood (entry, 4 and 8 weeks) and stifle synovial fluid (entry and 8 weeks) were obtained after BM-MSC injection. No adverse events after BM-MSC treatment were detected. Circulating CD8+ T lymphocytes were lower after BM-MSC injection. Serum C-reactive protein (CRP) was decreased at 4 weeks and serum CXCL8 was increased at 8 weeks. Synovial CRP in the complete CR stifle was decreased at 8 weeks. Synovial IFNγ was also lower in both stifles after BM-MSC injection. Synovial/serum CRP ratio at diagnosis in the partial CR stifle was significantly correlated with development of a second CR. Systemic and intra-articular injection of autologous BM-MSCs in dogs with partial CR suppresses systemic and stifle joint inflammation, including CRP concentrations. Intra-articular injection of autologous BM-MSCs had profound effects on the correlation and conditional dependencies of cytokines using causal networks. Such treatment effects could ameliorate risk of a second CR by modifying the stifle joint inflammatory response associated with cranial cruciate ligament matrix degeneration or damage.
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Peter
authors: P
authors: Muir
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Eric C
authors: EC
authors: Hans
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Molly
authors: M
authors: Racette
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Nicola
authors: N
authors: Volstad
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.|Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Susannah J
authors: SJ
authors: Sample
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Caitlin
authors: C
authors: Heaton
authors: UW Veterinary Care Hospital, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors: Gerianne
authors: G
authors: Holzman
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Susan L
authors: SL
authors: Schaefer
authors: Department of Medicine, School of Medicine & Public Health, University of Wisconsin-Madison, Madison, Wisconsin, 53705, United States of America.
authors: Debra D
authors: DD
authors: Bloom
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Jason A
authors: JA
authors: Bleedorn
authors: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Zhengling
authors: Z
authors: Hao
authors: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: Ermias
authors: E
authors: Amene
authors: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, 53706, United States of America.
authors: M
authors: M
authors: Suresh
authors: Department of Medicine, School of Medicine & Public Health, University of Wisconsin-Madison, Madison, Wisconsin, 53705, United States of America.|University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, 53705, United States of America.
authors: Peiman
authors: P
authors: Hematti
mesh_terms: D000818:Animals; D000070598:Anterior Cruciate Ligament Injuries / Q000276:immunology / Q000628:therapy*; D015415:Biomarkers / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology*; D002097:C-Reactive Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000628:therapy*; D004285:Dogs; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000662:veterinary*; D011446:Prospective Studies; D013582:Synovial Fluid / Q000276:immunology; D014182:Transplantation, Autologous / Q000662:veterinary; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007371:Interferon-gamma; D002097:C-Reactive Protein