Analysis of the kinetics of osteoclastogenesis in arthritic rats.
OBJECTIVE
To analyze the kinetics of osteoclastogenesis in 2 models of chronic immune-mediated arthritis and 1 model of acute arthritis.


METHODS
Adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in Lewis rats were used as models of chronic arthritis. Acute arthritis was induced in Lewis rats by injecting carrageenan into the hind paw. Osteoclasts were identified by cathepsin K immunohistochemistry at various time points after the onset of arthritis. The location, size, and nucleation of osteoclasts were also analyzed.


RESULTS
In both AIA and CIA, multinucleated and cathepsin K-positive osteoclasts first were observed on the day of disease onset. Initially, osteoclasts were localized at the periosteum next to the synovial membrane and in subchondral bone channels. The number, size, and nucleation of osteoclasts rapidly increased, leading to severe bone loss within days after disease onset. In addition, numerous mononucleated cathepsin K-positive osteoclast precursor cells emerged in the synovial membrane. All osteoclasts (cathepsin K-positive, multinucleated, attached to bone) and osteoclast precursors (cathepsin K-positive, mononucleated or multinucleated, within synovial tissue) were also positive for a macrophage-specific marker. Upon induction of acute arthritis with carrageenan, osteoclasts formed transiently in subchondral bone, but regressed 7 days after disease onset.


CONCLUSIONS
Functional osteoclasts are generated at the earliest stage of arthritis, and new precursors are continuously formed in the synovial membrane to replenish the osteoclast pool. These data indicate that anti-resorptive therapies may provide the most effective bone protection, when treatment is started soon after the onset of arthritis.
Schett
Georg
G
Amgen, Inc., Thousand Oaks, California 91320, USA.
Stolina
Marina
M
Bolon
Brad
B
Middleton
Scot
S
Adlam
Matt
M
Brown
Heather
H
Zhu
Li
L
Feige
Ulrich
U
Zack
Debra J
DJ
D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology*; D001862:Bone Resorption / Q000276:immunology / Q000473:pathology*; D002351:Carrageenan; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D005260:Female; D007596:Joints / Q000276:immunology / Q000473:pathology; D007700:Kinetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000276:immunology / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology*
D002351:Carrageenan; D002403:Cathepsins; D056657:Cathepsin K; C534133:Ctsk protein, rat