Human osteoarthritis cartilage-derived stromal cells activate joint degeneration through TGF-beta lateral signaling.

Wenguang Liu, Meng Feng, Chathuraka T Jayasuriya, Hang Peng, Long Zhang, Yingjie Guan, John A Froehlich, Richard M Terek, Qian Chen

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Dec

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Human osteoarthritis cartilage contains chondrocytes (OAC) and mesenchymal stromal cells (OA-MSC). Here, we found that TGF-β had different effects on OA-MSC and OAC, and revealed its lateral signaling mechanism in OA. RNAseq analysis indicated that OA-MSC expressed the same level of Bone Morphogenetic Protein (BMP) Receptor-1A as OAC but only 1/12 of Transforming Growth Factor beta (TGF-β) Receptor-1. While TGF-β specifically activated SMAD2 in OAC, it also activated BMP signaling-associated SMAD1 in OA-MSC. While TGF-β stimulated chondrogenesis in OAC, it induced hypertrophy, mineralization, and MMP-13 in OA-MSC. Inhibiting TGF-βR1 suppressed MMP-13 in OA-MSC but stimulated it in OAC. In contrast, by specifically targeting BMPR1A/ACVR1 in both cell types, LDN193189 inhibits cartilage degeneration through suppressing hypertrophy and MMP-13 in a mouse osteoarthritis model. Thus, LDN193189, a drug under development to inhibit constitutive BMP signaling during heterotopic ossification, may be re-purposed for OA treatment. © 2020 Federation of American Societies for Experimental Biology.

Citation

Wenguang Liu, Meng Feng, Chathuraka T Jayasuriya, Hang Peng, Long Zhang, Yingjie Guan, John A Froehlich, Richard M Terek, Qian Chen. Human osteoarthritis cartilage-derived stromal cells activate joint degeneration through TGF-beta lateral signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Dec;34(12):16552-16566