Beschreibung:
<jats:p>Tumor necrosis factor (TNF)-α is a key cytokine regulator of bone and precipitates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNFα is poorly defined. Here, we demonstrate that inactivating the pro-osteoblastogenic ERK activated ribosomal S6 kinase RSK2 leads to a drastically accelerated and amplified systemic bone loss in mice ectopically expressing TNF-α (human TNF transgenic, hTNFtg mice). The phenotype is associated with a decreased bone formation by osteoblasts which are strongly reduced in the hTNFtg mice lacking RSK2 as well as a drastic increased bone destruction by osteoclasts. The molecular basis is a cell autonomous increased sensitivity of osteoblasts as well as of osteocytes to TNF-induced apoptosis combined to an enhancement of their osteoclasts supportive activity. Thus, RSK2 exerts a strong negative regulatory loop on TNF-induced bone loss.</jats:p>