Abstract
Abstract 4052
Osteolytic bone disease is a major clinical burden in multiple myeloma. Uncoupling of normal homestatic bone remodelling by an increase in osteoclast numbers and suppression of osteoblasts is the main causative mechanism. Subgroups of patients, identified by recurrent IgH translocation partners and D-type cyclin expression, have different clinical features, including prevalence of bone disease. Molecular groups characterised by t(4:14) or t(14:16) translocations, have a lower incidence of lytic bone lesions when compared with subgroups characterised by t(11:14) and/or cyclin D1 expression. We hypothesize that while osteoclast activation is a common phenomenon, osteolysis depends upon the presence and degree of osteoblast suppression, which in turn is dictated by the underlying genetic lesion. We have recently established a medullary model of myeloma using the human KMS12BM cell line that bears t(11;14). This model exhibits lytic bone disease as evidenced by micro-computed-tomography (microCT) and histomorphometry, accompanied by increased osteoclastogenesis and suppressed osteoblast numbers. These features are typical of the clinical disease bearing t(11;14). In addition, we have established a second medullary model of an alternative molecular disease group using the MM1.s human myeloma cell line, bearing t(14;16). Non-irradiated β2M NOD/SCID mice intravenously injected with either the KMS12BM or MM1s cells develop tumours confined to the bone marrow with little extramedullary disease. Histomorphometric analysis of femora from diseased animals revealed several striking differences in bone biology between these two models. Early disease progression in the KMS12BM model is characterised by an increase in osteoblast numbers (p < 0.05) with little change in osteoclast numbers at trabecular surfaces. As homeostatic bone remodelling processes become uncoupled in advanced disease there is a loss of osteoblasts and an increase in osteoclast numbers. In contrast, in the MM1.s model, there are no significant changes in osteoblast or osteoclast numbers at the trabecular surfaces. The distinct impact of t(11:14) and t(14:16) modelled disease on bone is further illustrated by microCT analysis of femora of diseased animals. Femora of KMS12BM mice show a reduction in trabecular number and thickness (p < 0.05) with bone loss further highlighted by an increased structure model index (SMI, p < 0.05). MM1.s disease results in increased bone volume (p < 0.01) with a concordant increase in trabecular thickness (p < 0.05) and number (p < 0.01), and little change in SMI. Importantly, while bone disease in the KMS12BM model is typified by osteolytic lesions, MM1.s animals do not appear to develop osteolytic lesions, despite perturbation of bone biology. These models, representing distinct genetic subtypes of myeloma, produce different clinico-pathological effects on bone remodelling, perhaps by differential effects on osteoblast biology. They will facilitate the identification of critical molecular pathways involved in osteoblast suppression leading to bone loss.
Disclosures:
No relevant conflicts of interest to declare.
Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease
