Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease

Abstract

Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson’s linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

The Expression and Secretion Profile of TRAP5 Isoforms in Gaucher Disease

“…The degree and the nature of skeletal involvement in GD are variable, often associated with decreased BMD occurring at a young age, and accompanied by significant bone pain, disability, and reduced quality of life. TRAP5b has been described as a highly sensitive and specific diagnostic marker for osteopenia or osteoporosis and is related to bone-associated disorders, e.g., postmenopausal osteoporosis [53], rheumatoid arthritis [22,23], hyperparathyroidism [24], Paget's disease [54], or bone metastasis [25]. Recently, we demonstrated that TRAP5b could be used as a predictive biomarker of osteoporosis in GD [19].…”

“…The GBA1 genotypes included 17 patients with the homozygous p.N370S (N409S). The second most common allele was p.L444P (L483P) (n = 12); one patient had the L444P/L444P genotype (Supplemental Table S1 [19,22]). In the GD cohorts, the age range was from 18 to 68 years, with an average age of 42 ± 15 years.…”

“…The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cells13080716/s1, Supplementary Table S1. Demographics, genotypes, and clinical characteristics of bone disease in patients with GD which have previously been published [19,22]. Supplementary Table S2.…”

A Review on the Crosstalk between Insulin and Wnt/β-Catenin Signalling for Bone Health

“…High circulating levels of sclerostin and DKK1 have been associated with clinical bone pathologies, such as bone pain, structural bone changes, osteoporosis, and bone deformity. Thus, the circulated level of Wnt inhibitors are potential biomarkers of skeletal abnormalities [22]. In the absence of inhibitory control, the activation of the Wnt/β-catenin signalling pathway begins with the binding of the Wnt ligand to the membrane-bound frizzled family receptor and LRP4/5/6 to initiate a cellular response.…”

Biofabrication of an in-vitro bone model for Gaucher disease

“…Activators of bone resorption, DKK-1 and sclerostin, are elevated in GD, and sclerostin is associated with reduced bone mineral density, bone pain, bone marrow infiltration, and EM flask deformity [17]. Pharmacological inhibition of sclerostin and DKK-1 by monoclonal antibodies is one of the novel therapy for osteoporosis that is capable to promote new bone tissue growth [18][19][20].…”