Reduced Limb Length and Worsened Osteoarthritis in Adult Mice After Genetic Inhibition of p38 MAP Kinase Activity in Cartilage

Objective. MAP kinase p38 is part of an intracellular signaling pathway activated by environmental stress and inflammatory factors. Since in vitro studies show that inhibiting p38 activity leads to a reduction in the release of degenerative metalloproteinase from chondrocytes, we speculated that inactivation of p38 in vivo may be chondroprotective. To test this hypothesis, we examined the morphology of adult mice that express a dominant-negative (DN) p38 MAPK transgene in a cartilage-specific manner. Methods. The in vivo effects of the genetic inhibition of p38 MAPK activity in cartilage were investigated in 1-year-old heterozygous DN p38-transgenic mice (n = 10) using morphologic measurements, microfocal computed tomography scanning, biomechanical testing, and histologic analysis. Results were compared with those in wild-type (WT) littermates (n = 9). Results. Adult DN p38 MAPK(+/-) transgenic mice exhibited 50% p38 MAPK activity in articular chondrocytes as compared with WT mice. They were significantly shorter in overall body length as well as in the femur and tibia lengths. There were no differences in bone material or mechanical properties between the transgenic and WT mice. Surprisingly, the transgenic mice had higher grades of osteoarthritis of the knee joint. Conclusion. Genetic inhibition of p38 MAPK activity in cartilage results in shortened limb length and defects in the articular cartilage of the knee joints of adult mice. Our findings demonstrate that chronic life-long reduction of p38 MAPK activity may be harmful to joint health and suggest that the timing of p38 inhibition for chondroprotection in vivo is an important variable that warrants further investigation.