Morc3 mutant mice exhibit reduced cortical area and thickness, accompanied by altered haematopoietic stem cells niche and bone cell differentiation

Abstract

Morc3, a member of a highly conserved nuclear matrix protein super-family plays an important part in chromatin remodeling, DNA repair, epigenetic regulation and cellular senescence. However, its role in bone homeostasis is not known. In the present study, a phenotype-driven ENU mouse mutagenesis screen revealed that Morc3 mut +/− mice exhibit reduced cortical area and thickness with increased cortical porosity. Bone is a rigid organ, yet highly susceptible to metabolic changes throughout the adult life. Bone homeostasis is continuously maintained by the bone remodeling process which is tightly regulated by two key activities: bone removal by osteoclasts and bone matrix formation by osteoblasts. Imbalances in either bone resorption or bone formation can lead to clinical diseases like osteoporosis, osteopetrosis and Paget's disease of bone 1 . Worldwide direct and indirect annual costs of fracture due to osteoporosis have been estimated to be US$20 billion in the USA and about AUD$2.75 billion in Australia 2 . Despite recent advances in bone biology, the precise molecular mechanisms responsible for pathological bone conditions remain unclear. Therefore, elucidating the molecular mechanisms and novel molecules involved in the maintenance of bone homeostasis is crucial for the better understanding of skeletal health and development of novel therapeutics against various bone diseases.Morc3 (NXP2/KIAA0136/ZCWCC3) is a member of a highly conserved nuclear protein super-family, with characteristic domains that directly link the Morc proteins to signaling-dependent chromatin remodeling and epigenetic regulation 3 . Mapping of functional domains revealed it as a nuclear matrix protein with a putative RNA binding site in a nuclear matrix binding domain which is vital for transcription regulation 4 . Similar to other GHKL (gyrase, Hsp90, histidine kinase, MutL)-ATPase family members, Morc3 forms a homodimer through GHKL-ATPase and coiled-coil domains in an ATP-binding-dependent manner 5 . It functions as a molecular clamp through the ATPase cycle to form Morc3 nuclear domains in a PML (promyelocytic leukemia)-independent manner. The CW-type Zinc Finger domain of Morc3 is required for proper localization

Retracted: The Role of MicroRNA‐143‐5p in the Differentiation of Dental Pulp Stem Cells into Odontoblasts by Targeting Runx2 via the OPG/RANKL Signaling Pathway

“…Comparisons of cell migration among the six groups by Transwell assay. Note: Ã , compared with the blank group, P < 0.05; miR-143-5p, microRNA-143-5p; Runx2, runt-related transcription factor 2. crucial role in the signaling pathway of osteoclast differentiation [Jadhav et al, 2016;Ujiie et al, 2016]. Runx2, as a specific transcription factor can activate the differentiation of bone marrow mesenchymal cells into osteoblasts, which further regulates the maturation of osteoblasts as well as expression of OPG [Baek et al, 2014;Nagatake et al, 2015].…”

Dermatomyositis and Immune-Mediated Necrotizing Myopathies: A Window on Autoimmunity and Cancer

“…MORC3 interacts with ROR1, a tyrosine kinase involved in pre-B cell receptor signaling pathway promoting cell proliferation ( 133 ). Finally, MORC3 plays a role in the transduction of calcium homeostasis regulator and is involved in bone remodeling ( 134 ).…”

Mechanism for autoinhibition and activation of the MORC3 ATPase

“…Originally identified as an autoantigen in inflammatory myopathies (1)(2)(3), it has since been linked to other autoimmune disorders, Down syndrome, and cancer (4)(5)(6)(7). Studies using mouse models show that knockout of Morc3 is perinatally lethal, and partial loss of Morc3 results in changes in bone calcium homeostasis and up-regulation of inflammatory pathways (8). In cells, MORC3 has been found to localize to promyelocytic leukemia nuclear bodies (PML-NBs) and is implicated in the recruitment of p53 to PML-NBs to induce cellular senescence (9,10).…”