title: Consequences of daily administered parathyroid hormone on myeloma growth, bone disease, and molecular profiling of whole myelomatous bone.
abstract: BACKGROUND
  Induction 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.
  
  
  RESULTS
  We 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
  We 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.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Pennisi
authors.forename: Wen
authors.initials: W
authors.lastname: Ling
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Sharmin
authors.initials: S
authors.lastname: Khan
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015519:Bone Density; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D010006:Osteoblasts / Q000166:cytology; D010014:Osteolysis; D010281:Parathyroid Hormone / Q000494:pharmacology*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010281:Parathyroid Hormone; D051153:Wnt Proteins