Abstract
Monocyte-derived cells were shown to promote cartilage repair in osteoarthritis. The role of the long non-coding RNA (lncRNA) MM2P in this function of monocyte-derived cells remained unexplored. Treatment of RAW264.7 murine macrophages and mouse bone marrow-derived macrophages with IL-4 or IL-13 upregulated MM2P expression, upstream of STAT3 and STAT6 phosphorylation. Specifically, MM2P blocked SHP2-mediated dephosphorylation of STAT3 at Try705 and interacted with the RNA-binding protein FUS. In turn, p-STAT3 increased the Sox9 gene expression. These cells released Sox9 mRNA and protein-containing exosomes, as demonstrated by a transmission electron microscope, nanoparticle tracking analysis, and detection of typical surface markers. Their culture supernatant promoted the differentiation of mouse primary chondrocytes, i.e., upregulated the expression of Col1a2 and Acan genes and promoted the secretion of extracellular matrix components proteoglycan and type II collagen. These effects were mediated by Sox9 mRNA and protein delivered to chondrocytes by exosomes. Together, ex vivo treatment of monocyte-derived cells with IL-4 or IL-13 promoted chondrocyte differentiation and functions through exosome-mediated delivery of Sox9 mRNA and protein.
Highlights
Osteoarthritis (OA) is the most common degenerative disorder of the joint, which is mainly attributed to an imbalance between repair and breakdown of the joint tissues or abnormal endochondral ossification due to mechanical loading[1,2]
MM2P facilitated M2 polarization To confirm the function of MM2P in M2 polarization of
MM2P interacted with FUS to stabilize SRY-box transcription factor 9 (SOX9) messenger RNAs (mRNAs) We identified the protein bands in the pulldown product of MM2P, and found that FUS interacted with MM2P (Fig. 7a and Supplementary Table 1)
Summary
Osteoarthritis (OA) is the most common degenerative disorder of the joint, which is mainly attributed to an imbalance between repair and breakdown of the joint tissues or abnormal endochondral ossification due to mechanical loading[1,2]. The activated innate immune cells, especially macrophages, participate in OA progression[8]. Macrophages can be activated by certain biomaterials to release specific cytokines and possess immunomodulatory impacts on in vitro tissue recovery and osteogenic differentiation[9,10,11].
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