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Fig. 1 | Arthritis Research & Therapy

Fig. 1

From: Smad-dependent mechanisms of inflammatory bone destruction

Fig. 1

Osteoclasts arise from hematopoietic monocyte/macrophage precursors upon interaction of RANKL with its receptor RANK. Both are key regulators of bone remodelling and essential for the development, activation and survival of osteoclasts. Binding of RANKL to RANK leads to the recruitment of TRAF6, which activates Akt (survival), NF-κB and the mitogen-activated protein kinases p38, ERK and JNK, resulting in the induction of the transcription factors c-Jun, c-Fos and NFATc1, all crucial for osteoclast differentiation. As an important signalling cascade promoting the RANKL-induced osteoclastogenesis, the Smad signalling pathway, which can be activated by transforming growth factor (TGF)-β family members, including TGF-β, activin and myostatin, has been identified. By way of example, myostatin signals through the ActRIIB-ALK4/5 heterodimer to activate Smad2/3, which subsequently translocates directly to the nuclear compartment or binds first to NFATc1 and then translocates into the nucleus, both leading to enhanced expression of several osteoclast-specific target genes, including NFATc1 itself. Smad-mediated translocation of c-Fos, which has been demonstrated upon TGF-β stimulation during RANKL-mediated osteoclastogenesis is also indicated in the figure. ECM extracellular matrix, Ub ubiquitin

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