Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation.
OBJECTIVE
To investigate how the time of initiation influences the effects of estrogen therapy on type II collagen (CII) turnover and the structural integrity of articular cartilage in ovariectomized rats and to determine whether estrogen exerts direct effects on the catabolic function of chondrocytes ex vivo.


METHODS
A total of 46 Sprague-Dawley rats were distributed into 1 of the following treatment groups: 1) ovariectomy, 2) ovariectomy plus early estrogen therapy, 3) ovariectomy plus delayed estrogen therapy, or 4) sham operation. Cartilage turnover was estimated by measuring the serum levels of C-telopeptide of type II collagen (CTX-II). Cartilage lesions at week 9 were quantified using a published scoring technique. The presence of the CTX-II epitope in articular cartilage was assessed by immunohistochemistry. The effects of estrogen (1-100 nM) on chondrocytes were investigated in bovine cartilage explants subjected to catabolic cytokines (tumor necrosis factor alpha [TNFalpha] and oncostatin M [OSM]).


RESULTS
In ovariectomized rats, estrogen therapy evoked significant decreases in serum CTX-II independently of the time of initiation; yet, delayed initiation resulted in diminished efficacy in terms of preventing cartilage lesions. CTX-II fragments were present in articular cartilage, colocalizing with early lesions at the cartilage surface. In untreated animals, the early relative increases in serum CTX-II were proportional to the severity of cartilage lesions at week 9 (r = 0.73, P < 0.01). Estrogen significantly and dose-dependently countered CTX-II release from TNFalpha plus OSM-stimulated cartilage explants ex vivo.


CONCLUSIONS
Our results suggest that estrogen counters the acceleration of CII degradation and related structural alterations, and these benefits can be maximized by early initiation after menopause. The protective effect of estrogen seems to involve direct inhibition of the catabolic function of chondrocytes.
Oestergaard
Svetlana
S
Nordic Bioscience, Herlev, Denmark. soe@nordicbioscience.com
Sondergaard
Bodil C
BC
Hoegh-Andersen
Pernille
P
Henriksen
Kim
K
Qvist
Per
P
Christiansen
Claus
C
Tankó
László B
LB
Karsdal
Morten A
MA
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000097:blood; D024043:Collagen Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004958:Estradiol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D010052:Ovariectomy; D010455:Peptides / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013264:Stifle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D024042:Collagen Type I; D024043:Collagen Type II; D004338:Drug Combinations; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C052929:collagen type I trimeric cross-linked peptide; D004958:Estradiol