Changes Of Wnt Pathway - Related Factors In Patients With Primary Hypertrophic Osteoarthritis And Changes Of COX - 2 Inhibitor After Intervention

BackgroundPrimary hypertrophic osteoarthropathy (PHO) is a rare congenital disease characterized by the triad of digital clubbing, periostosis and pachydermia. According to molecular findings in recent years, PHO is categorized into two subtypes:1) hypertrophic osteoarthropathy, primary, autosomal recessive, type 1 (PHOAR1), caused by hypdroxyprostaglandin dehydrogenase (HPGD) deficiency; 2) hypertrophic osteoarthropathy, primary, autosomal recessive, type 2 (PHOAR2), caused by solute carrier organic anion transporter family, member 2A1 (SLCO2A1) deficiency. Either HPGD or SLCO2A1 deficiency can lead to failure of prostaglandin E2 (PGE2) degradation, while these two subtypes have similar clinical phenotypes as well as distinct features including onset age, sex ratio and complications. Wingless-type (Wnt) signaling is an important pathway in bone metabolism. Wnt-signaling inhibitors including sclerostin and dickkopf-1 (Dkk-1) might play a role in PHO pathogenesis. Cyclo-oxygenase (COX) is a key enzyme in PGE2 production, and COX-2 selective inhibitor could decrease PGE2 levels thus making it an option for PHO treatment. But researches on COX-2 inhibitor efficacy and side effects in PHO patients are limited.Objective1. To analyze the clinical manifestations of 27 PHO patients.2. To compare the clinical characteristics of two PHO subtypes and explore the underlying mechanism.3. To measure sclerostin and Dkk-1 levels in PHO patients, and understand the role of Wnt-signaling in PHO pathogenesis.4. To evaluate the efficacy and side effects of COX-2 inhibitor in PHO patients.Subjects and Methods1. Subjects:27 PHO patients in Endocrinology Department of PUMCH.2. Methods:(1) PHO clinical characteristics were summarized based on clinical records, biochemical measurements and X-ray examinations.(2) HPGD and SLCO2A1 gene mutations were analyzed by PCR technique and direct nucleotide sequencing.(3) Sclerostin and Dkk-1 levels were measured by enzyme-linked immunosorbent assay (ELISA).(4) Patients enrolled were given COX-2 selective inhibitor (Etoricoxib,60mg once daily) and evaluated at several time points (baseline,1,3,6 and 12 months).Results1. The clinical characteristics of 27 PHO patients were summarized. Most patients presented with the typical PHO triad of digital clubbing (100%), periostosis (100%) and panchydermia (85.2%), while palmar/plantar hyperhidrosis and joint swelling are also common. Complications including diarrhea and anemia were also found. As for biochemical measurements, most patients presented with elevated inflammatory markers and high serum and urinary PGE2. Periostosis and acro-osteolysis are typical radiological features for PHO.2. Seven PHOAR1 patients with HPGD mutations and 20 PHOAR2 patients with SLCO2A1 mutations were compared. Two subtypes showed differences in sex ratio, onset age, acro-osteolysis severity, serum and urinary PGEM and complications.3. Although the baseline sclerostin level was similar to healthy controls, it increased with COX-2 inhibitor treatment. PHO patients had low Dkk-1 level, which decreased at the beginning of COX-2 inhibitor treatment and increased during the following treatment.4. Selective COX-2 inhibitors showed efficacy in alleviating PHO symptoms including digital clubbing, panchydermia and joint swelling without severe side effects. It can also decrease the inflammatory markers and PGE2 levels. But symptoms would recurrent if the treatment is discontinued.Conclusion1. We summarized the clinical characteristics in the biggest sample of PHO in Chinese population.2. Comparison between two subtypes of PHO showed significant difference in clinical features and biochemical characteristics.3. Low Dkk-1 levels in PHO patients suggested the relationship between Wnt-signaling pathway and PHO pathogenesis.4. Selective COX-2 inhibitor is an effective symptomatic therapy for PHO.