The roles of Runx1 in skeletal development and osteoarthritis: A concise review

Abstract

Runt-related transcription factor-1 (Runx1) is well known for its functions in hematopoiesis and leukemia but recent research has focused on its role in skeletal development and osteoarthritis (OA). Deficiency of the Runx1 gene is fatal in early embryonic development, and specific knockout of Runx1 in cell lineages of cartilage and bone leads to delayed cartilage formation and impaired bone calcification. Runx1 can regulate genes including collagen type II (Col2a1) and X (Col10a1), SRY-box transcription factor 9 (Sox9), aggrecan (Acan) and matrix metalloproteinase 13 (MMP-13), and the up-regulation of Runx1 improves the homeostasis of the whole joint, even in the pathological state. Moreover, Runx1 is activated as a response to mechanical compression, but impaired in the joint with the pathological progress associated with osteoarthritis. Therefore, interpretation about the role of Runx1 could enlarge our understanding of key marker genes in the skeletal development and an increased understanding of Runx1 could be helpful to identify treatments for osteoarthritis. This review provides the most up-to-date advances in the roles and bio-mechanisms of Runx1 in healthy joints and osteoarthritis from all currently published articles and gives novel insights in therapeutic approaches to OA based on Runx1.

Keywords: Bone; Chondrogenesis; Gene therapy; Osteoarthritis; Osteogenesis; Runx1; Skeletal development.

Figure 1

The structure of Runx1. The abbreviations are as follows: NT, N-terminus; CT, C-terminus; AD: activation domain; ID: inhibitory domain; QA, glutamine/alanine-rich sequence. The Runx family of transcription factors contains three members, and they share RHD, AD and ID domains, and C-terminus VWRPY motif. The transcriptional functions of Runx1 are enhanced with the combination of other molecules.

Figure 2

The binding sites of Runx1 on the promoter of genes. Runx1 can directly bind to the promoter of other genes, regulating their expression. Some genes have more than one Runx binding sites. The white box indicates the binding sites on the promoter while the black box indicates the coding sequence.

Figure 3

Runx1 and CBFβ. a. Runx1 protein and core binding factor β (CBFβ) form the heterodimerization of core-binding factor (CBF) and regulate the promoter of other genes. Runx1 protein is the DNA-binding subunit and CBFβ plays the role of stablizing Runx1 and enhancing the DNA-binding function of Runx1. b. Comparison among the control group, CBFβ^{fl/fl/M−Cre} group, and CBFβ(Δch/Δch) group. CBFβ^{fl/fl/M−Cre}, mesenchymal-cell-specific CBFβ-deficient mice including Prrx1-Cre and Twist-Cre; CBFβ(Δch/Δch), chondrocyte-specific CBFβ-deficient mice including Sox9-Cre and Col2a1-Cre. Compared with the control group, CBFβ^{fl/fl/M−Cre} group and CBFβ (Δch/Δch) group both have fewer and thinner trabecular bones, delayed bone development and ossification, and fewer osteoblasts. In CBFβ^{fl/fl/M−Cre} group, the ossification reduces, the growth plates shorten, the cartilage resting zones elongate, the chondrocytes shape abnormally, and the number of osteoblasts are significantly reduced, while that of osteoclasts remain unchanged. In CBFβ(Δch/Δch) group, the proliferative chondrocytes increase, with no hypertrophic zones.

Figure 4

The signaling pathway of Runx1 related to chondrogenesis and osteogenesis. a. The difference in bone or chondrocytes when Runx1 is deficient or overexpressed. In mice deficient of Runx1, proliferation factors in chondrocytes decrease, and the differentiation of bone marrow mesenchymal cells into osteoblasts and chondrocytes is inhibited through low expression of related genes. In mice overexpressed with Runx1, the proliferation factors and chondeogenic genes increase, thus inhibiting cell hypertrophy and promoting cell proliferation. Ihh, Indian hedgehog; PTH1R, parathyroid hormone-related peptide receptor; OCN, osteocalcin; OPN, osteopontin; Osx, Osterix; Atf4, activating transcription factor 4; Col2a1, collagen type II; Col10a1, collagen type X; MMP-13, matrix metalloproteinase-13; ACAN, aggrecan; Sox9, sex-determining region Y-type high mobility group box protein 9. b. Other signaling pathways related to Runx1 and bone. Transforming growth factor-beta1 (TGF-β1) and bone morphogenetic proteins (BMPs) regulate chondrogenesis via Smad-dependent signal pathways and Runx1 helps to phosphorylate Smad2/3. Moreover, all-trans retinoic acid (ATRA), insulin-like growth factor 1 (IGF1), protein phosphatase 5 (PP5) can increase the expression of Runx1 through different signal pathways. Runx1 can then upregulate the expression of ACAN, Col2a1, Col10a1, OPN and OCN. c. The interplay of Runx1 and Sox proteins is complex. Runx1 protein and Sox9 protein influence each other mutually. Sox5 and Sox6 are the downstream targets of Runx1 and Sox9.

Figure 5

The signaling pathway of Runx1 related to osteoarthritis.