Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis.
OBJECTIVE
Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA.


METHODS
The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age-related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels.


RESULTS
Intraarticular injections of ribose enhanced cartilage AGE levels approximately 5-fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more-pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more-severe OA in animals with enhanced AGE levels.


CONCLUSIONS
These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.
DeGroot
Jeroen
J
Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands. j.degroot@pg.tno.nl
Verzijl
Nicole
N
Wenting-van Wijk
Marion J G
MJ
Jacobs
Kim M G
KM
Van El
Benno
B
Van Roermund
Peter M
PM
Bank
Ruud A
RA
Bijlsma
Johannes W J
JW
TeKoppele
Johan M
JM
Lafeber
Floris P J G
FP
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016118:Anterior Cruciate Ligament / Q000473:pathology / Q000601:surgery; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D010003:Osteoarthritis / Q000453:epidemiology* / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors
D017127:Glycation End Products, Advanced