DUSP5 Promotes Osteogenic Differentiation Through SCP1/2-Dependent Phosphorylation of SMAD1

Abstract

Dual-specificity phosphatases (DUSPs) are defined by their capability to dephosphorylate both phosphoserine/phosphothreonine (pSer/pThr) and phosphotyrosine (pTyr). DUSP5, a member of DUSPs superfamily, is located in the nucleus and plays crucially regulatory roles in the signaling pathway transduction. In our present study, we discover that DUSP5 significantly promotes osteogenic differentiation of mesenchymal stromal cells (MSCs) by activating SMAD1 signaling pathway. Mechanistically, DUSP5 physically interacts with the phosphatase domain of small C-terminal phosphatase 1/2 (SCP1/2, SMAD1 phosphatases) by the linker region. In addition, we further confirm that DUSP5 activates SMAD1 signaling through a SCP1/2-dependent manner. Specifically, DUSP5 attenuates the SCP1/2-SMAD1 interaction by competitively binding to SCP1/2, which is responsible for the SMAD1 dephosphorylation, and thus results in the activation of SMAD1 signaling. Importantly, DUSP5 expression in mouse bone marrow MSCs is significantly reduced in ovariectomized (OVX) mice in which osteogenesis is highly passive, and overexpression of Dusp5 via tail vein injection reverses the bone loss of OVX mice efficiently. Collectively, this work demonstrates that the linker region of DUSP5 maybe a novel chemically modifiable target for controlling MSCs fate choices and for osteoporosis treatment.

Ataluren Prevented Bone Loss Induced by Ovariectomy and Aging in Mice Through the BMP-SMAD Signaling Pathway

“…Taken together, this evidence suggests that ataluren may act in the targeted management of hBMMSC osteogenic differentiation. Furthermore, the transcriptome sequencing analysis results showed that 50 µM ataluren upregulated DUSP5 most signi cantly, which elevated MSC osteogenic differentiation through the BMP-SMAD pathway, as demonstrated by our group previously (45). It was also suggested that DUSP5 overexpression inhibits NF-κB pathway activation and thereby controls in ammation (46).…”

“…3b). DUSP5 has been suggested to enhance MSC osteogenic differentiation through the BMP-SMAD pathway (Liu et al, 2021). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed the most signi cant enrichment in the transforming growth factor beta (TGF-β) signaling pathway (Fig.…”

Downregulation of METTL14 improves postmenopausal osteoporosis via IGF2BP1 dependent posttranscriptional silencing of SMAD1

“…aortic valve interstitial cells, periodontal ligament stem cells, and adipose tissue-derived stem cells [25][26][27][28]. Importantly, SMAD1 is involved in OP by promoting the osteogenesis of BSMCs [25,29]. Meanwhile, SMAD1 at phosphorylation can be detected in osteoclasts and has been proven to be vital in osteoclast differentiation and activity [30].…”

DUSP5 and PHLDA1 mutations in mature cystic teratomas of the ovary identified on whole-exome sequencing may explain teratoma characteristics

“…DUSP5 protein plays an important role in the maintenance of pluripotency in mouse embryonic stem cells and may be required for embryoid body development [ 32 ]. DUSP5 promotes osteogenic differentiation through SCP1/2-dependent phosphorylation of SMAD1 [ 33 ]. MPP2 gene encodes palmitoylated membrane protein 2, which is a member of the membrane-associated scaffold protein family known as MAGUKs (membrane-associated guanylate kinase homologs) [ 34 ].…”

“…Another interesting finding in this study is the mutation p.Ala220Met of the DUSP5 gene in all teratomas. DUSP5 protein plays an important role in the maintenance of stem cell pluripotency [ 32 ] and osteogenic differentiation [ 33 ]. Osteogenic differentiation is another characteristic of teratomas, i.e., bone or tooth formation.…”