title: Novel chondrogenic and chondroprotective effects of the natural compound harmine.
abstract: A significant number of natural compounds have been shown to regulate the behavior of the cells, in collaboration with cellular proteins. CCN2/connective tissue growth factor (CTGF) has been reported to have essential roles in cartilage development, chondrocyte proliferation and differentiation as well as regulation of the extracellular matrix metabolism. Previous studies demonstrated the capability of CCN2 to regenerate surgical defects in articular cartilage of rat knee. Also, transgenic mice over-expressing cartilage-specific CCN2 were shown to be more resistant to aging-related cartilage degradation. We hypothesized that small molecules that induce CCN2 in chondrocytes could be novel candidates to increase the resistance to aging-related cartilage degradation, or even to correct cartilage degenerative changes incurred in OA. Therefore, this study screened a compound library and identified the β-carboline alkaloid harmine as a novel inducer of CCN2 in human chondrocytic HCS-2/8 cells and osteoarthritic articular chondrocytes. Harmine increased the expression of the cartilage markers aggrecan and COL2α1, as well as that of the master regulator of chondrogenesis, SOX-9. Moreover, harmine notably induced chondrogenesis of prechondrocytic ATDC5 cells in micromass cultures. The chondroprotective effect of harmine was investigated under inflammatory condition by stimulation with TNFα, and harmine was shown to ameliorate TNFα-induced decrease in expression of CCN2 and cartilage markers. These findings uncover novel chondrogenic effects of harmine and indicate harmine as a potential drug for prevention and/or repair of cartilage degradation.
authors.affiliation: Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8525, Japan.
authors.forename: Emilio Satoshi
authors.initials: ES
authors.lastname: Hara
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ono
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubota
authors.forename: Wataru
authors.initials: W
authors.lastname: Sonoyama
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Oida
authors.forename: Takako
authors.initials: T
authors.lastname: Hattori
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Furumatsu
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ozaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takigawa
authors.forename: Takuo
authors.initials: T
authors.lastname: Kuboki
mesh_terms: D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020219:Chondrogenesis / Q000187:drug effects; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006247:Harmine / Q000494:pharmacology*; D006801:Humans; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020011:Protective Agents / Q000494:pharmacology*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053674:Aggrecans; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; C526317:CCN2 protein, human; C499177:COL2A1 protein, human; D024043:Collagen Type II; D020011:Protective Agents; D055758:SOX9 Transcription Factor; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor; D006247:Harmine