Runx1 protects against the pathological progression of osteoarthritis

Chenchen Zhou,Daimo Guo,Yueyi Yang,Yi Fan,Demao Zhang,Jing Xie,Jing Zou,Yujia Cui,Xiaobing Li

doi:10.1038/s41413-021-00173-x

Chenchen Zhou, Daimo Guo + Show 7 more

Open Access

https://doi.org/10.1038/s41413-021-00173-x

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Abstract

Runt-related transcription factor-1 (Runx1) is required for chondrocyte-to-osteoblast lineage commitment by enhancing both chondrogenesis and osteogenesis during vertebrate development. However, the potential role of Runx1 in joint diseases is not well known. In the current study, we aimed to explore the role of Runx1 in osteoarthritis induced by anterior cruciate ligament transaction (ACLT) surgery. We showed that chondrocyte-specific Runx1 knockout (Runx1f/fCol2a1-Cre) aggravated cartilage destruction by accelerating the loss of proteoglycan and collagen II in early osteoarthritis. Moreover, we observed thinning and ossification of the growth plate, a decrease in chondrocyte proliferative capacity and the loss of bone matrix around the growth plate in late osteoarthritis. We overexpressed Runx1 by adeno-associated virus (AAV) in articular cartilage and identified its protective effect by slowing the destruction of osteoarthritis in cartilage in early osteoarthritis and alleviating the pathological progression of growth plate cartilage in late osteoarthritis. ChIP-seq analysis identified new targets that interacted with Runx1 in cartilage pathology, and we confirmed the direct interactions of these factors with Runx1 by ChIP-qPCR. This study helps us to understand the function of Runx1 in osteoarthritis and provides new clues for targeted osteoarthritis therapy.

Highlights

Runt-related transcription factor-1 (Runx1), which is known as core-binding factor α 2 or acute myeloid leukemia 1 (AML1), is known for its vital role in hematopoiesis and blood malignancies.[1]In humans, the RUNX1 gene is one of the most common targets of genetic alterations in acute leukemia.[2]
We examined the expression of collagen examined the important role of Runx[1] in OA and its potential X (ColX, Fig. 2i), which is a marker of hypertrophic cartilage, and therapeutic effect in a mouse model from a genetics perspective. found that the distribution of ColX was limited to chondrocyte clusters, which might be due to the serious loss of the surrounding ossifying matrix
In the mouse anterior cruciate ligament transaction (ACLT)-OA model by scoring cartilage destruction (OARSI grade, 0–6), synovitis (0–3), osteophyte maturity (0–3), and Runx[1] overexpression alleviates the pathological progression of subchondral bone plate (SBP) thickness (Fig. 1i) and found more growth plate cartilage in the late stage of osteoarthritis serious knee joint destruction in the Runx1-conditional knockout (CKO) OA groups than in We examined the effect of associated virus (AAV)-Runx[1] overexpression on the the WT OA groups

Summary

Introduction

Runt-related transcription factor-1 (Runx1), which is known as core-binding factor α 2 or acute myeloid leukemia 1 (AML1), is known for its vital role in hematopoiesis and blood malignancies.[1]In humans, the RUNX1 gene is one of the most common targets of genetic alterations in acute leukemia.[2]. Wang et al found that overexpression of Runx[1] induced BMSCs to undergo chondrogenic differentiation.[10]

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