IL-6 is not required for parathyroid hormone stimulation of RANKL expression, osteoclast formation, and bone loss in mice.
Continuous elevation of parathyroid hormone (PTH) increases osteoclast precursors, the number of osteoclasts on cancellous bone, and bone turnover. The essential molecular mediators of these effects are controversial, however, and both increased receptor activator of NF-kappaB ligand (RANKL) and IL-6 have been implicated. The goal of these studies was to determine whether continuous elevation of endogenous PTH alters IL-6 gene expression in vivo and whether IL-6 is required for PTH-induced bone loss. To accomplish this, we generated transgenic mice harboring a luciferase reporter gene under the control of IL-6 gene regulatory regions to allow accurate quantification of IL-6 gene activity in vivo. In these mice, induction of secondary hyperparathyroidism using a calcium-deficient diet did not alter IL-6-luciferase transgene expression, whereas RANKL mRNA expression was elevated in bone tissue. Moreover, secondary hyperparathyroidism induced an equivalent amount of bone loss in wild-type and IL-6-deficient mice, and PTH elevated RANKL mRNA and osteoclast formation to the same extent in bone marrow cultures derived from wild-type and IL-6-deficient mice. These results demonstrate that IL-6 is not required for the osteoclast formation and bone loss that accompanies continuous elevation of PTH.
O'Brien
Charles A
CA
Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. caobrien@uams.edu
Jilka
Robert L
RL
Fu
Qiang
Q
Stewart
Scott
S
Weinstein
Robert S
RS
Manolagas
Stavros C
SC
D015502:Absorptiometry, Photon; D000818:Animals; D015152:Blotting, Northern; D015519:Bone Density / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006651:Histocytochemistry; D006961:Hyperparathyroidism / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism*; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D010281:Parathyroid Hormone; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse