AG490 mediates osteoclast survival through activation of AKT and ERK

• Published in: The FASEB journal 2007, Vol.21 (6), p.LB11-LB11
• Main Authors: Sun, Hyun Min, Kwak, Han Bok, Yang, Daum, Jeong, Kyoung Suk, Lee, Zang Hee
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.6.LB11-b

Osteoclasts are multinucleated cells with the unique ability to resorb bone. Elevated activity of these cells under pathological conditions leads to the progression of bone erosion, such as osteoporosis, periodontal disease, and rheumatoid arthritis. The regulation of osteoclast apoptosis is important for bone homeostasis. In this study, we examined the effect of AG490 (JAK2 specific inhibitor) on osteoclast apoptosis. We show that AG490 inhibits cytochrome c release into cytosol and in turn suppresses caspase‐9 and ‐3 activation, thereby inhibiting osteoclast apoptosis. Also, AG490 stimulated the phosphorylation of ERK and Akt. Adenovirus‐mediated overexpression of dominant negative (DN)‐Ras and DN‐Akt in osteoclasts inhibited the survival of osteoclast despite the presence of AG490. Thus, osteoclast survival in response to AG490 leads to ERK and Akt pathways. In contrast, AG490 inhibits the phosphorylation of ERK and Akt in osteoclast precursors and mediates apoptosis. Furthermore, constitutive active (CA)‐MEK and CA‐Akt suppress the release of cytochrome c into cytosol and inhibit caspase activity. In addition, AG490 mediates bone erosion in vivo. These results suggest that AG490 inhibits caspase activity by activating Akt and ERK and in turn suppresses the apoptosis of osteoclasts.