Mesenchymal gaucho homing on the range

Type 1 (nonneuronopathic) Gaucher disease (GD1) is caused by an inherited deficiency of glucocerebrosidase. The clinical manifestations are heterogeneous and include hematologic cytopenias, hepatomegaly, splenomegaly, and sometimes disabling skeletal pathology. Pharmacologic treatments (intravenous enzyme replacement therapy and oral substrate depletion therapy) ameliorate the hematologic, visceral, and skeletal manifestations of GD1 with resultant gains in quality of life.³  Attention has now focused on the long-term morbidity including late-emerging Parkinsonian syndromes, persistent osteopenia/osteoporosis, and GD1-associated malignancies, particularly myeloma and lymphoma. Defining the complex impact of glucocerebrosidase deficiency and abnormal glycosphingolipid metabolism on the ecology of the skeletal microenvironment is essential for development of effective treatment and prevention strategies for patients with GD1.

The cause of bone mineral loss in GD1 patients is unclear. There are no consistent abnormalities in OPG-RANKL or in the classic markers of bone formation and resorption. Although most GD1 patients have had bone marrow biopsies, histomorphometry is rarely done. Reduced numbers of CD8 cells reportedly correlate with GD1 bone involvement, but it is uncertain whether this is a primary or secondary phenomenon.⁴  Adipocytes are significant players in bone metabolism, but little is known about the interactions between Gaucher cells and fat cells and how they might influence bone mineralization. Altered glucose metabolism, insulin resistance, and abnormal adiponectin levels that may affect bone mineralization have been reported in untreated GD1 patients, but their clinical importance is unclear. Increased blood levels of macrophage-derived osteoclastogenic cytokines MIP-α and MIP-β may also contribute to both general and focal GD1 skeletal manifestations.⁵ 

As to myeloma and lymphoma, hypotheses have focused on the sphingolipid storage process itself as contributory to chronic antigenic stimulation or as an autocrine and/or paracrine stimulus to the production of cytokines and cellular growth factors.¹  Abnormal T-cell lectin responses and decreased numbers of CD4, NK, and dendritic cells have been reported.⁶  Gaucher cells, characterized as alternatively activated macrophages, may secrete IL-10, a cytokine linked to development of osteopenia and myeloma. Other proinflammatory cytokines that influence bone homeostasis, B-cell differentiation, and plasma cell growth are variably abnormal in GD1 patients.⁵  Proinflammatory macrophages that are recruited by and cluster with Gaucher cells are a likely source, but involvement by other cells is theoretically possible.

Mesenchymal stromal cells (MSCs) are nonhematopoietic stem cells with the capacity for self-renewal as well as differentiation into various connective tissue cells including osteoblasts and fat cells. Age-related MSC dysfunction has been related to osteoporosis, and an infusion of MSCs causes T-cell, NK-cell, and dendritic cell depletion.⁷  The report of Campeau et al offers preliminary evidence that MSCs contribute to GD1 pathology. The authors studied cultured bone marrow MSCs from a GD1 patient who relapsed after an 18-month treatment interruption. Although GD1 MSCs were in many ways indistinguishable from normal cells, there was a 3-fold increase in cellular glucosyl ceramide and a marked increase in COX-2, prostaglandin E2, IL-8, and CCL2. A similar alteration in the cytokine and prostaglandin pattern was observed when normal MSCs were treated with conduritol-B-epoxide (a potent, noncompetitive glucocerebrosidase inhibitor).

The authors speculate that the glucocerebrosidase-deficient MSC secretome may be relevant to the skeletal and neoplastic anomalies associated with GD1. MSC may home to sites of bone microinjury and, via a strong multicytokine signal, recruit monocytes and stimulate osteoclastogenesis resulting in osteolytic lesions and generalized bone mineral loss. CCL2 is also a chemoattractant for normal and malignant plasma cells that may be recruited to a marrow environment where exposure to Gaucher cell–derived IL-10 (another cytokine related to myeloma and possibly up-regulated by MSC-secreted PGE2) creates a milieu conducive to malignant proliferation. Parenthetically, IL-17, a cytokine known to be increased in GD1 patients and that is associated with inflammation, bone resorption, and myeloma, stimulates the proliferation of human MSCs.⁸ 

Hughes¹  recently noted the limits in our current knowledge of the pathogenesis of GD1, and posited that “only hypothesis generation beyond current paradigms will allow more complete understanding and ultimately rational intervention for the diverse aspects of this disorder.” The work presented by Campeau et al fits this prescription, but it is based on material from a single patient. GD1 phenotypes are notoriously heterogeneous. Many more patients will need to be studied before “the skies are not cloudy all day.”