Inhibition of BMP-Smad1/5 signaling with DMH1 attenuates joint degeneration in a rat model of cuff tear arthropathy.

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.