title: Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model.
abstract: OBJECTIVE
  To determine whether ascorbic acid might be of benefit for the treatment of spontaneous osteoarthritis (OA) when administered over a long period of time.
  
  
  METHODS
  We investigated the effects of 8 months' exposure to low, medium, and high doses of ascorbic acid on the in vivo development of histologic knee OA in the male Hartley guinea pig. The low dose represented the minimum amount needed to prevent scurvy. The medium dose was the amount present in standard laboratory guinea pig chow and resulted in plasma levels comparable with those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily). The high dose was the amount shown in a previous study of the guinea pig to slow the progression of surgically induced OA.
  
  
  RESULTS
  We found an association between ascorbic acid supplementation and increased cartilage collagen content but, in contrast to findings in a previous study of surgically induced OA in the guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active transforming growth factor beta (TGF beta) was expressed in marginal osteophytes, whose size and number were significantly increased with increasing intake of ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a biomarker of cartilage turnover, corroborated the histologic findings.
  
  
  CONCLUSIONS
  Ascorbic acid has been shown to activate latent TGF beta. Prolonged intraarticular exposure to TGF beta has been shown to cause OA-like changes. We found expression of active TGF beta in osteophytes, a prominent feature of the joint histology seen in association with ascorbic acid treatment. Thus, the deleterious effects of prolonged ascorbic acid exposure may be mediated in part by TGF beta. This worsening of OA with ascorbic acid supplementation suggests that ascorbic acid intake should not be supplemented above the currently recommended dietary allowance (90 mg/day for men and 75 mg/day for women).
authors.affiliation: Duke University Medical Center, Durham, North Carolina 27710, USA. vbk@acpub.duke.edu
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
authors.forename: Janet L
authors.initials: JL
authors.lastname: Huebner
authors.forename: Thomas
authors.initials: T
authors.lastname: Stabler
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Flahiff
authors.forename: Lori A
authors.initials: LA
authors.lastname: Setton
authors.forename: Christian
authors.initials: C
authors.lastname: Fink
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vilim
authors.forename: Amy G
authors.initials: AG
authors.lastname: Clark
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000097:blood / Q000494:pharmacology*; D015519:Bone Density; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006168:Guinea Pigs; D016018:Least-Squares Analysis; D008297:Male; D064235:Matrilin Proteins; D020370:Osteoarthritis, Knee / Q000473:pathology / Q000503:physiopathology*; D012614:Scurvy / Q000517:prevention & control; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015430:Weight Gain
chemical_list: D000975:Antioxidants; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D001205:Ascorbic Acid