Generation of osteoclasts from type 1 Gaucher patients and correlation with clinical and genetic features of disease

Gaucher disease (GD) is a rare autosomal recessive disorder caused by deficient activity of β-glucocerebrosidase resulting in the accumulation of glucosylceramide. Bone disease is a common feature with radiological evidence in up to 93% of patients. Severity of bone involvement ranges from osteoporosis to pathological fractures. The progressive course of type 1 GD is largely mitigated by treatment with enzyme replacement therapy (ERT) or substrate reduction. A number of studies have shown some patients suffer bone events while receiving ERT. Studies of biochemical markers of bone turnover have generated varied results and as a consequence are not generally used to assess bone disease in GD. In vitro osteoclast generation from peripheral blood samples of 74 Gaucher patients followed over a period of up to 10 years was correlated with bone events, reports of bone pain, anaemia, spleen status, bone mineral density, chitotriosidase activity, treatment with Gaucher specific therapies, bisphosphonates, mutation status and severity. Osteoclast generation, enumerated when cultured on glass, was significantly higher when differentiated from the peripheral blood of Gaucher patients which reported bone pain (116.4 ± 18.0 vs 69.0 ± 8.6, p < 0.01), had anaemia (153.7 ± 34.9 vs 78.5 ± 8.8, p < 0.01), had a splenectomy (137.6 ± 41.1 vs 60.8 ± 13.0, p < 0.05), versus those who did not. Osteoclast generation was also indicative of in vivo Gaucher specific therapy response as those naïve to therapy generated significantly more osteoclasts than those on therapy (111.2 ± 35.8 vs 45.1 ± 10.3, p < 0.05), as did patients receiving therapy but still suffering bone events (125.1 ± 31.37 vs 45.1 ± 10.33, p < 0.05). These findings demonstrate that the in vitro osteoclast assay may be a useful method for following bone disease progression in Gaucher patients.