Examining the impact of bone pathology on type I Gaucher disease

Gaucher disease (GD) is an autosomal recessively inherited lysosomal disorder caused by mutations in GBA gene leading to deficient activity of the lysosomal enzyme acid glucocerebrosidase. Phenotipically, three different forms can be distinguished, type I GD being the most frequent, and characterized by the absence of involvement of the CNS. Affected organs are the spleen, liver, bone marrow and bone and, in severe cases, also the lung and kidney. Bone manifestations include bone pain, bone crises, osteopenia, osteoporosis, avascular necrosis and pathological fractures. Nowadays, skeletal alterations are the major cause of morbidity for patients, and a major concern for physicians who treat them, owing to the variable grade of response and refractoriness of bone pathology to treatment. Pathological mechanisms of bone alterations in GD are still poorly understood. Advances are being achieved in the knowledge of cellular and molecular mechanisms; by application of basic knowledge from osteoimmunology. GD as well as other lysosomal disorders is associated to a chronic stimulation of the immune system, especially the innate arm. Cellular alteration produces a proinflammatory milieu leading to enhancement of the activity of osteoclasts, the main degradative/resorptive cell of bone. This article focuses on the details of bone alterations, effect of therapies on skeletal pathology and our current state of knowledge of the complex pathophisiology of this orphan disease.