Abstract
Lamin A/C, intermediate filament proteins from the nuclear lamina encoded by the LMNA gene, play a central role in mediating the mechanosignaling of cytoskeletal forces into nucleus. In fact, this mechanotransduction process is essential to ensure the proper functioning of other tasks also mediated by lamin A/C: the structural support of the nucleus and the regulation of gene expression. In this way, lamin A/C is fundamental for the migration and differentiation of mesenchymal stem cells (MSCs), the progenitors of osteoblasts, thus affecting bone homeostasis. Bone formation is a complex process regulated by chemical and mechanical cues, coming from the surrounding extracellular matrix. MSCs respond to signals modulating the expression levels of lamin A/C, and therefore, adapting their nuclear shape and stiffness. To promote cell migration, MSCs need soft nuclei with low lamin A content. Conversely, during osteogenic differentiation, lamin A/C levels are known to be increased. Several LMNA mutations present a negative impact in the migration and osteogenesis of MSCs, affecting bone tissue homeostasis and leading to pathological conditions. This review aims to describe these concepts by discussing the latest state-of-the-art in this exciting area, focusing on the relationship between lamin A/C in MSCs’ function and bone tissue from both, health and pathological points of view.
Highlights
The nuclear lamina, a thin protein network lining the inner surface of the nuclear envelope, is primarily composed of type V intermediate filaments known as A- and B-type lamins
Cellular and molecular signaling pathways, in addition to microenvironmental changes, have been studied in order to understand the role of cytokines, growth factors, extracellular matrix molecules and transcription factors [86] that regulate the differentiation of mesenchymal stem cells (MSCs) toward a specific cell type
The different characteristics of MSCs pinpoint them as crucial tools to elucidate the mechanisms governing bone repair and disorders
Summary
The nuclear lamina, a thin protein network lining the inner surface of the nuclear envelope, is primarily composed of type V intermediate filaments known as A- and B-type lamins. The MSCs surrounding the area differentiate into osteoblasts, beginning to synthesize extracellular bone matrix rich in type I collagen This process will proceed until all cartilaginous tissue is replaced by bone tissue. Lamin A overexpression in mouse pre-osteoblastic MC3T3-E1 cells has been shown to promote osteoblast differentiation and calcification by inducing the expression of: alkaline phosphatase, type I collagen, BSP, OCN and dentin matrix acidic phosphoprotein 1 (DMP-1), in the presence of bone morphogenetic protein 2 (BMP-2) growth factor [32]. Taken together, all this evidence reveals the crucial role lamin. These processes are highly determinate by lamin A/C implication for their correct accomplishment [43]
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