Osteoarthritis and cartilage open · 2026
Inhibition of BMP-Smad1/5 signaling with DMH1 attenuates joint degeneration in a rat model of cuff tear arthropathy.
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Iuchi Tomohiro, Shimanoe Kento, Ide Takayuki, Takada Seiya, Saho Suguru, Uekama Kohei, Masuda Yusuke, Tawaratsumida Hiroki, Ijuin Toshiro, Tominaga Hiroyuki, Maeda Shingo, Taniguchi Noboru
Аннотация
OBJECTIVE: To characterize bone morphogenetic protein (BMP) signaling in cuff tear arthropathy (CTA) using a modified rat model (mCTA) and determine whether inhibition of DMH1-sensitive BMP type I receptor signaling attenuates CTA pathology.
DESIGN: The rat mCTA model was generated by resection of the supraspinatus and infraspinatus tendons, the superior joint capsule, and the long head of the biceps tendon. Single-cell RNA sequencing (scRNA-seq) was performed to characterize BMP ligand expression in the humeral head. BMP-2, BMP-7, and phosphorylated Smad1/5 (p-Smad1/5) were evaluated by immunohistochemistry, and Id1 expression was assessed by RT-qPCR. Synovial macrophage subsets were assessed by immunostaining. Rats received daily intraperitoneal DMH1 (10 mg/kg) or vehicle for 4 weeks. Histological scores, bone volume, osteoclast number, inflammatory cytokines, catabolic enzymes, and macrophage markers were quantified.
RESULTS: scRNA-seq revealed expression of BMP ligands. In mCTA cartilage, BMP-2 and BMP-7 expression, p-Smad1/5 signaling, and hypertrophic markers (Runx2, Col10a1) were upregulated. DMH1 suppressed Smad1/5 activation, reduced inflammatory and catabolic gene expression, and attenuated cartilage degeneration. In subchondral bone, BMP signaling was associated with increased osteoclast numbers, RANKL/OPG imbalance, and reduced bone volume, all of which were improved by DMH1 treatment. In the synovium, BMP signaling and inflammatory mediators were elevated with increased macrophage numbers; DMH1 reduced inflammatory mediators and M1 macrophage numbers.
CONCLUSIONS: BMP-Smad1/5 signaling is activated in multiple joint tissues in mCTA and is associated with cartilage degeneration, subchondral bone resorption, and synovial inflammation. These findings suggest that BMP-Smad1/5 signaling may contribute to the pathological changes observed in mCTA.
DESIGN: The rat mCTA model was generated by resection of the supraspinatus and infraspinatus tendons, the superior joint capsule, and the long head of the biceps tendon. Single-cell RNA sequencing (scRNA-seq) was performed to characterize BMP ligand expression in the humeral head. BMP-2, BMP-7, and phosphorylated Smad1/5 (p-Smad1/5) were evaluated by immunohistochemistry, and Id1 expression was assessed by RT-qPCR. Synovial macrophage subsets were assessed by immunostaining. Rats received daily intraperitoneal DMH1 (10 mg/kg) or vehicle for 4 weeks. Histological scores, bone volume, osteoclast number, inflammatory cytokines, catabolic enzymes, and macrophage markers were quantified.
RESULTS: scRNA-seq revealed expression of BMP ligands. In mCTA cartilage, BMP-2 and BMP-7 expression, p-Smad1/5 signaling, and hypertrophic markers (Runx2, Col10a1) were upregulated. DMH1 suppressed Smad1/5 activation, reduced inflammatory and catabolic gene expression, and attenuated cartilage degeneration. In subchondral bone, BMP signaling was associated with increased osteoclast numbers, RANKL/OPG imbalance, and reduced bone volume, all of which were improved by DMH1 treatment. In the synovium, BMP signaling and inflammatory mediators were elevated with increased macrophage numbers; DMH1 reduced inflammatory mediators and M1 macrophage numbers.
CONCLUSIONS: BMP-Smad1/5 signaling is activated in multiple joint tissues in mCTA and is associated with cartilage degeneration, subchondral bone resorption, and synovial inflammation. These findings suggest that BMP-Smad1/5 signaling may contribute to the pathological changes observed in mCTA.