Pioglitazone and metformin attenuate hemophilic arthropathy progression via peroxisome proliferator-activated...

Hemophilic arthropathy poses major clinical challenges. Joint bleeding leads to iron deposition, inflammation, and synovial hyperplasia, causing joint damage. Nevertheless, the mechanisms involved in the disease progression needs deeper exploration so that effective intervention can be proposed.

We aimed at investigating the relevant signaling pathways in hemophilic arthropathy pathogenesis and evaluate potential therapeutic measures through targeted regulatory approach.

Hemophilia (H)A rats were used as the experimental model. To mimic arthropathy caused by joint bleeding in hemophilic patients, we induced joint hemorrhage with a needle puncture method. RNA-sequencing was carried out to identify transcriptomic alterations associated with tissue damage of arthropathy, and drug treatment protocols were tested in these HA rats. Outcomes were assessed via joint swelling measurements and histopathological examination.

We identified, through RNA-sequencing, the activation of peroxisome proliferator-activated receptors (PPAR) signaling pathway as a possible protective factor in hemophilic arthropathy, potentially mediated by PPARγ upregulation and subsequent suppression of inflammatory pathways. Three treatment protocols were designed, namely, pioglitazone (30 mg/kg/d), metformin (150 mg/kg/d), and combination treatment of pioglitazone (15 mg/kg/d) and metformin (150 mg/kg/d). These treatments were administered for 3 days, starting either 3 days before or immediately after hemorrhage induction. Although none of these treatments alleviated spontaneous bleeding phenotypes in HA rats, they were found to effectively prevent and attenuate early-stage hemophilic arthropathy. These treatments were well-tolerated in preclinical studies.

The treatment for PPAR signaling activation shows potential for preventing and managing early hemophilic arthropathy and may be tried in patients to reduce disability risk.