Activating transcription factor 4 regulates osteoclast differentiation

Skeletal integrity requires a delicate balance between osteoblast and osteoclast activity. Excessive osteoclastogenesis results in bone destruction whereas reduced osteoclastogenesis causes osteopetrosis. Osteoclasts originate from cells of the monocyte/macrophage lineage and their formation and maturation is tightly regulated. M-Csf is a growth factor which regulates the early phase of osteoclast lineage commitment. Binding of M-Csf to its receptor on bone marrow monocytes activates Pi3k/Akt signaling pathway and Rank gene transcription. Then, Rank ligand binds to Rank on osteoclast precursors and induces the expression of Nfat1c, a crucial transcriptional factor for osteoclast differentiation. Activating transcriptional factor 4 (Atf4) is a critical factor for osteoblasts differentiation, but its cell autonomous function in osteoclast differentiation has not been studied.

Cao et al. [1] evaluated the function of Atf4 in osteoclastogenesis. They first demonstrated that Atf4 was expressed by bone marrow monocytes and that Atf4-/- mice had reduced osteoclasts number. In vitro, bone monocytes from Atf4-/- mice displayed reduced osteoclastic differentiation even in the presence of wild type osteoblasts or exogenous Rank ligand. Conversely, mice overexpressing Atf4 specifically in osteoclasts showed increased osteoclast number and osteopenia. The authors then questioned the molecular pathways that regulates osteoclast differentiation downstream Atf4. Atf4 invalidation resulted in reduced expression of Nfat1c in cultured bone marrow monocytes. Accordingly, Atf4 overexpression had the opposite effect. Nfat1c overexpression rescued in vitro osteoclasts differentiation of Atf4-/- monocytes, confirming its instrumental role downstream Atf4. The authors further demonstrated that Nfat1c was a direct target of Atf4 and that M-Csf was the upstream regulator of Atf4.

The results of this study establish that Atf4 plays a direct and critical role in regulating osteoclast differentiation.

1. Cao, H et al. J Clin Invest. 2010;120: 2755-2766.