gp130 in late osteoblasts and osteocytes is required for PTH-induced osteoblast differentiation

Abstract

Parathyroid hormone (PTH) treatment stimulates osteoblast differentiation and bone formation, and is the only currently approved anabolic therapy for osteoporosis. In cells of the osteoblast lineage, PTH also stimulates the expression of members of the interleukin 6 (IL-6) cytokine superfamily. Although the similarity of gene targets regulated by these cytokines and PTH suggest cooperative action, the dependence of PTH anabolic action on IL-6 cytokine signaling is unknown. To determine whether cytokine signaling in the osteocyte through glycoprotein 130 (gp130), the common IL-6 superfamily receptor subunit, is required for PTH anabolic action, male mice with conditional gp130 deletion in osteocytes (Dmp1Cre.gp130 f/f ) and littermate controls (Dmp1Cre.gp130 w/w ) were treated with hPTH(1-34) (30 mg/kg 5! per week for 5 weeks). PTH dramatically increased bone formation in Dmp1Cre.gp130 w/w mice, as indicated by elevated osteoblast number, osteoid surface, mineralizing surface, and increased serum N-terminal propeptide of type 1 collagen (P1NP). However, in mice with Dmp1Cre-directed deletion of gp130, PTH treatment changed none of these parameters. Impaired PTH anabolic action was associated with a 50% reduction in Pth1r mRNA levels in Dmp1Cre.gp130 f/f femora compared with Dmp1Cre.gp130 w/w . Furthermore, lentiviral-Cre infection of gp130 f/f primary osteoblasts also lowered Pth1r mRNA levels to 16% of that observed in infected C57/BL6 cells. In conclusion, osteocytic gp130 is required to maintain PTH1R expression in the osteoblast lineage, and for the stimulation of osteoblast differentiation that occurs in response to PTH. IntroductionIntermittent administration of parathyroid hormone (PTH) to animal models and humans (teriparatide (Forteo)) increases bone mass (Reeve et al. 1980, Neer et al. 2001, Lindsay et al. 2007, and is the only approved treatment for osteoporosis capable of inducing bone formation (reviewed in Hodsman et al. (2005) and Khosla et al. (2008)). However, the mechanisms by which intermittent PTH increases bone mass remain unclear, and identifying downstream targets of this pathway may aid in the design of improved anabolic therapies. Journal of EndocrinologyResearch Printed in Great BritainPublished by Bioscientifica Ltd.The effects of PTH on bone mass are likely to be mediated by cells of the osteoblast lineage. This lineage includes committed pre-osteoblasts, matrix-producing osteoblasts, bone lining cells, and matrix-embedded osteocytes. PTH acts directly at each stage of differentiation, as follows. PTH promotes pre-osteoblast differentiation (Dobnig & Turner 1995), inhibits osteoblast apoptosis (Jilka et al. 1999), and reactivates quiescent lining cells to become active osteoblasts (Kim et al. 2012). PTH also acts directly on osteocytes to reduce their expression of the WNT antagonist sclerostin, an inhibitor of bone formation (Bellido et al. 2005, Keller & Kneissel 2005.PTH also stimulates the expression of receptor activator of NF-kappa-B ligand (RANKL) by early osteoblast li...

MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation

“…RPS6KB1, an effector of the PI3K (phosphatidylinositol 3-kinase) pathway important for ROS downstream signaling, was increased in a CKD rat model on a high calcium-phosphate diet, developing vascular calcification and VSMC differentiation to osteoblast-like cells in combination with IL-6 and TNF [48]. IL6ST is as an important factor during osteoblast differentiation in response to PTH in mice [49]. …”

Dynamic interplay between bone and multiple myeloma: Emerging roles of the osteoblast

“…The mouse cell line MC3T3-E1 [47] is a well-accepted albeit unique pre-osteoblast cell line that undergoes linear osteogenic differentiation. Primary mouse calvarial osteoblasts are also widely used [48], but studies with mouse osteoblasts add some risk of missing human cell-specific signaling.…”

Cardiotrophin-like cytokine factor 1 (CLCF1) and neuropoietin (NP) signalling and their roles in development, adulthood, cancer and degenerative disorders

“…Although in situ detection has not been carried out in adult tissue, CLCF1, CRLF1 and CNTFR (but not NP) mRNAs are detected in cultured murine primary osteoblasts [12,49]. Both CRLF1 and CLCF1 mRNA levels in osteoblasts are stimulated by parathyroid hormone [49], an agent that stimulates bone formation when used therapeutically, and that has been shown to be dependent on gp130 signalling within the osteoblast lineage to have this effect [50]. Surprisingly however, upregulation of CLCF1 and CRLF1 is not generalizable to all activities that stimulate bone formation, since CLCF1 and CRLF mRNA levels are lowered in bones subjected to mechanical loading [51].…”