title: Cissus quadrangularis inhibits IL-1β induced inflammatory responses on chondrocytes and alleviates bone deterioration in osteotomized rats via p38 MAPK signaling.
abstract: BACKGROUND
  Inflammatory mediators are key players in the pathogenesis of osteoarthritis (OA) and bone destruction. Conventional drugs suppress symptomatic activity and have no therapeutic influence on disease. Cissus quadrangularis and Withania somnifera are widely used for the treatment of bone fractures and wounds; however, the cellular and molecular mechanisms regulated by these herbals are still unclear.
  
  
  METHODS
  We established an in vitro OA culture model by exposing human chondrocytes to proinflammatory cytokine and interleukin (IL)-1β for 36 hours prior to treatment with the herbals: C. quadrangularis, W. somnifera, and the combination of the two herbals. Cell viability, toxicity, and gene expression of OA modifying agents were examined. In addition, expression of survivin, which is crucial for cell growth, was analyzed. In vivo work on osteotomized rats studied the bone and cartilage regenerative effects of C. quadrangularis, W. somnifera, and the combination therapy.
  
  
  RESULTS
  Exposure of chondrocytes to IL-1β induced significant toxicity and cell death. However, herbal treatment alleviated IL-1β induced cell toxicity and upregulated cell growth and proliferation. C. quadrangularis inhibited gene expression of cytokines and matrix metalloproteinases, known to aggravate cartilage and bone destruction, and augmented expression of survivin by inhibiting p38 MAPK. Interestingly, osteotomized rats treated with C. quadrangularis drastically enhanced alkaline phosphatase and cartilage tissue formation as compared to untreated, W. somnifera only, or the combination of both herbals.
  
  
  CONCLUSIONS
  Our findings demonstrate for the first time the signaling mechanisms regulated by C. quadrangularis and W. somnifera in OA and osteogenesis. We suggest that the chondroprotective effects and regenerative ability of these herbals are via the upregulation of survivin that exerts inhibitory effects on the p38 MAPK signaling pathway. These findings thus validate C. quadrangularis as a potential therapeutic for rheumatic disorders.
authors.affiliation: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Geelong Technology Precinct (GTP), Deakin University, Waurn Ponds, VIC, Australia.
authors.forename: Jagat R
authors.initials: JR
authors.lastname: Kanwar
authors.affiliation: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Geelong Technology Precinct (GTP), Deakin University, Waurn Ponds, VIC, Australia.
authors.forename: Rasika M
authors.initials: RM
authors.lastname: Samarasinghe
authors.affiliation: Ayurvedic College, Paprola, Kangra, Himachal Pradesh, India.
authors.forename: Kuldeep
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Ayurvedic College, Paprola, Kangra, Himachal Pradesh, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Arya
authors.affiliation: Ayurvedic College, Paprola, Kangra, Himachal Pradesh, India.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang, Malaysia.
authors.forename: Sreenivasan
authors.initials: S
authors.lastname: Sasidharan
authors.affiliation: Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Geelong Technology Precinct (GTP), Deakin University, Waurn Ponds, VIC, Australia.
authors.forename: Rupinder K
authors.initials: RK
authors.lastname: Kanwar
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001847:Bone Diseases / Q000517:prevention & control*; D002470:Cell Survival; D019902:Chondrocytes / Q000187:drug effects*; D032422:Cissus / Q000737:chemistry*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010027:Osteotomy; D010936:Plant Extracts / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D000893:Anti-Inflammatory Agents; D006025:Glycosaminoglycans; D053583:Interleukin-1beta; D010936:Plant Extracts; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Withania somnifera; alternative therapy; cytokines; herbal; inflammation; osteoarthritis