Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Abstract

The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b− bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α–induced expression of specific cytokines, such as CXCL5, IL-1β, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.

Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice

“…( 72 ) This phenotype was solely explained by impaired bone formation without affecting osteoclastogenesis. ( 73 ) We observed a similar phenotype in the Shank2 −/− mice due to decrease in osteoblastogenesis, whereas osteoclastogenesis remains unaffected. Because Sharpin is a downstream target of Shank2 , it is reasonable to anticipate that Shank2 might exert these phenotypic effects through altered Sharpin complexes.…”

SHARPIN stabilizes estrogen receptor α and promotes breast cancer cell proliferation

“…SHARPIN depletion will impair the linear ubiquitination of IKKr, which will cripple the P65/P50 translocation into the nuclear [ 37 ]. Phenotypically, SHARPIN knockout mice present with chronic proliferative dermatitis and impaired B and T cell development [ 38 – 40 ]. However, less is known about SHARPIN function in human cancer, even it endure a high gene amplification in TCGA database, such as pancreatic cancer and breast cancer ( http://www.cbioportal.org ).…”

High-Throughput Screening for Linear Ubiquitin Chain Assembly Complex (LUBAC) Selective Inhibitors Using Homogenous Time-Resolved Fluorescence (HTRF)-Based Assay System

“…In the absence of LUBAC components, NF-κB signaling is attenuated and induces apoptosis and inflammation. [5][6][7][8] Many studies on the pathophysiological functions of LUBAC, including B-and T-cell development, innate and adaptive immune response, [9][10][11][12][13][14] carcinogenesis, 15 and osteogenesis 16 in humans, have recently been performed. However, the relevance and functions of LUBAC in pathogenesis remain controversial.…”