Erk5 in mesenchymal stem cells maintains bone homeostasis in adulthood

Abstract

We previously clarified that Extracellular signal-regulated kinase 5 (Erk5) directly phosphorylates Smad specific E3 ubiquitin protein ligase 2 (Smurf2) at Thr²⁴⁹ (Smurf2^Thr249), which leads to activating its ubiquitin ligase activity. Although we have demonstrated that Erk5 in embryonic mesenchymal stem cells (MSCs) is necessary for proper skeletogenesis, its role in adult bone marrow (BM)-MSCs on bone homeostasis remains unknown. It has been reported that Leptin receptor-positive (LepR⁺) BM-MSCs represent a major source of bone in adult bone marrow. Here, we unveiled the importance of Erk5 in BM-MSCs as a critical regulator of bone homeostasis in adulthood. Mice lacking Erk5 in LepR⁺ BM-MSCs showed osteosclerotic bone marrow with age in vivo. Erk5 deficiency increased differentiation of BM-MSCs toward osteoblasts along with a higher expression of transcription factors for osteogenic differentiation in vitro. Erk5 deficiency decreased Smurf2^Thr249 phosphorylation, and subsequently increased Smad1/5/8-dependent signaling in BM-MSCs. Genetic induction of the phosphomimetic mutant of Smurf2 rescued the osteosclerotic phenotype in Erk5-deficient mice. These findings suggest that the Erk5–Smurf2^Thr249 axis in BM-MSCs plays an essential role in maintaining proper bone homeostasis in adult bone marrow.