Osteoblast Differentiation and Signaling: Established Concepts and Emerging Topics

Abstract

Osteoblasts, the cells that build up our skeleton, are remarkably versatile and important cells that need tight regulation in all the phases of their differentiation to guarantee proper skeletal development and homeostasis. Although we know many of the key pathways involved in osteoblast differentiation and signaling, it is becoming clearer and clearer that this is just the tip of the iceberg, and we are constantly discovering novel concepts in osteoblast physiology. In this review, we discuss well-established pathways of osteoblastic differentiation, i.e., the classical ones committing mesenchymal stromal cells to osteoblast, and then osteocytes as well as recently emerged players. In particular, we discuss micro (mi)RNAs, long non-coding (lnc)RNAs, circular (circ)RNAs, and extracellular vesicles, focusing on the mechanisms through which osteoblasts are regulated by these factors, and conversely, how they use extracellular vesicles to communicate with the surrounding microenvironment.

Keywords: extracellular vesicles; miRNAs; non-coding RNAs; osteoblast differentiation.

Figure 1

Conventional osteogenic differentiation pathways. Cartoon showing the two classical osteogenic differentiation pathways of MSCs/preosteoblasts, i.e., the bone morphogenic pathway and the Wnt/β-catenin pathway. BMPRs—BMP receptors; BAMBI—BMP and activin membrane-bound inhibitor homolog; CRIM1—cysteine-rich motor neuron 1 protein; SMAD—small mothers against decapentaplegic; DKK1—Dickkopf-related protein 1; sFRP2—secreted frizzled-related protein 2; Kremen—Kringle domain-containing transmembrane protein; LRP—Low Density Lipoprotein Receptor-Related Protein; GSK—glycogen synthase kinase; CKIα—casein kinase Iα; APC—adenomatous polyposis coli; TCF/LEF—T-cell factor/lymphoid enhancer-binding factor. Created with biorender.com.

Figure 2

MSC differentiation. Cartoon showing the possible differentiation fates of mesenchymal stem cells. Created with biorender.com.

Figure 3

Novel players in osteogenesis. Cartoon listing the non-coding RNAs and extracellular vesicles described in the review. Macs—macrophages; OCs—osteoclasts; OP/OA—osteoporotic/osteoarthritic patients; MSTN—myostatin; OCy—osteocytes. Created with biorender.com.