Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes.
OBJECTIVE
Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions.


METHODS
Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks.


RESULTS
The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P<0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P<0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P<0.001) decrease in CTX-II levels.


CONCLUSIONS
These results are the first evidence of calcitonin receptor expression on articular chondrocytes and that the chondroprotective effects of calcitonin might involve the inhibition of MMP expression.
Nordic Bioscience Diagnostics, Herlev, Denmark.
B C
BC
Sondergaard
H
H
Wulf
K
K
Henriksen
S
S
Schaller
S
S
Oestergaard
P
P
Qvist
L B
LB
Tankó
Y Z
YZ
Bagger
C
C
Christiansen
M A
MA
Karsdal
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002116:Calcitonin / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000737:chemistry / Q000201:enzymology*; D002417:Cattle; D019902:Chondrocytes / Q000737:chemistry / Q000378:metabolism*; D024042:Collagen Type I / Q000097:blood; D024043:Collagen Type II / Q000378:metabolism*; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053683:Oncostatin M / Q000494:pharmacology; D010052:Ovariectomy; D010455:Peptides / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018003:Receptors, Calcitonin / Q000032:analysis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015415:Biomarkers; D024042:Collagen Type I; D024043:Collagen Type II; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D018003:Receptors, Calcitonin; D014409:Tumor Necrosis Factor-alpha; C052929:collagen type I trimeric cross-linked peptide; D053683:Oncostatin M; C028815:salmon calcitonin; D002116:Calcitonin; D020782:Matrix Metalloproteinases