The dynactin subunit DCTN1 controls osteoclastogenesis via the Cdc42/PAK2 pathway

Bone remodeling: Regulatory protein identified A critical mechanism for maintaining bone health uncovered by scientists in South Korea could provide insights into bone disease development. Bone remodeling is a lifetime process of bone generation that ensures bones remain healthy. Osteoclasts (OC), cells that break down bone, differentiate from white blood cell populations. Disruption to OC formation and function plays a critical role in bone diseases, yet the regulatory mechanisms in OC generation are unclear. Hong-Hee Kim at Seoul National University and co-workers investigated the role of a protein called DCTN1, which is involved in skeletal assembly processes. The team found that inhibiting DCTN1 suppressed the expression of key proteins needed for OC formation in cell cultures and mouse models. Overexpressing DCTN1 was equally damaging, suggesting the protein plays a key regulatory role. Osteoclasts (OCs), cells specialized for bone resorption, are generated from monocyte/macrophage precursors by a differentiation process governed by RANKL. Here, we show that DCTN1, a key component of the dynactin complex, plays important roles in OC differentiation. The expression of DCTN1 was upregulated by RANKL. The inhibition of DCTN1 expression by gene knockdown suppressed OC formation, bone resorption, and the induction of NFATc1 and c-Fos, critical transcription factors for osteoclastogenesis. More importantly, the activation of Cdc42 by RANKL was inhibited upon DCTN1 silencing. The forced expression of constitutively active Cdc42 restored the OC differentiation of precursors with DCTN1 deletion. In addition, PAK2 was found to be activated by RANKL and to function downstream of Cdc42. The DCTN1-Cdc42 axis also inhibited apoptosis and caspase-3 activation. Furthermore, the anti-osteoclastogenic effect of DCTN1 knockdown was verified in an animal model of bone erosion. Intriguingly, DCTN1 overexpression was also detrimental to OC differentiation, suggesting that DCTN1 should be regulated at the appropriate level for effective osteoclastogenesis. Collectively, our results reveal that DCTN1 participates in the activation of Cdc42/PAK2 signaling and the inhibition of apoptosis during osteoclastogenesis.