Abstract
BackgroundInduction of osteolytic bone lesions in multiple myeloma is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates.Methodology/Principal FindingsWe tested the effects of daily administered parathyroid hormone (PTH) on bone disease and myeloma growth, and we investigated molecular mechanisms by analyzing gene expression profiles of unique myeloma cell lines and primary myeloma cells engrafted in SCID-rab and SCID-hu mouse models. PTH resulted in increased bone mineral density of myelomatous bones and reduced tumor burden, which reflected the dependence of primary myeloma cells on the bone marrow microenvironment. Treatment with PTH also increased bone mineral density of uninvolved murine bones in myelomatous hosts and bone mineral density of implanted human bones in nonmyelomatous hosts. In myelomatous bone, PTH markedly increased the number of osteoblasts and bone-formation parameters, and the number of osteoclasts was unaffected or moderately reduced. Pretreatment with PTH before injecting myeloma cells increased bone mineral density of the implanted bone and delayed tumor progression. Human global gene expression profiling of myelomatous bones from SCID-hu mice treated with PTH or saline revealed activation of multiple distinct pathways involved in bone formation and coupling; involvement of Wnt signaling was prominent. Treatment with PTH also downregulated markers typically expressed by osteoclasts and myeloma cells, and altered expression of genes that control oxidative stress and inflammation. PTH receptors were not expressed by myeloma cells, and PTH had no effect on myeloma cell growth in vitro.Conclusions/SignificanceWe conclude that PTH-induced bone formation in myelomatous bones is mediated by activation of multiple signaling pathways involved in osteoblastogenesis and attenuated bone resorption and myeloma growth; mechanisms involve increased osteoblast production of anti-myeloma factors and minimized myeloma induction of inflammatory conditions.
Highlights
Multiple myeloma (MM), a hematologic malignancy of terminally differentiated plasma cells, is closely associated with induction of osteolytic bone disease and skeletal complications in .80% of patients
Whereas bone mineral density (BMD) of the myelomatous bones in saline-treated hosts was reduced by 1465%, it was increased by 1062% in parathyroid hormone (PTH)-treated hosts (p,0.002 saline vs. PTH-treated hosts); for both treatment groups, effects were similar in SCID-rab and SCID-hu mice
Positive effects of PTH on preventing MM bone disease and promoting bone anabolism were associated with reduced growth of Hg myeloma cells, which was assessed by measuring human monoclonal immunoglobulins (hIg) in mice sera, in SCID-rab mice (Figure 1C) and SCID-hu mice (Figure 1F)
Summary
Multiple myeloma (MM), a hematologic malignancy of terminally differentiated plasma cells, is closely associated with induction of osteolytic bone disease and skeletal complications in .80% of patients. Bisphosphonates reduce skeletal complications, bone disease often progresses [6,7], indicating that osteoclastogenesis is only partially inhibited and that suppression of osteoblastogenesis plays a vital role in uncoupling the bone remodeling process in MM [8,9,10,11]. Infusion of mesenchymal stem cells into myelomatous bones was associated with reduced tumor burden [15]. These studies suggest that treating MM with osteoblastactivating agents could simultaneously help control bone disease and myeloma cell growth. Current management of myeloma bone disease is limited to the use of antiresorptive agents such as bisphosphonates
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