Parathyroid hormone (PTH), a circulating factor, stimulates osteoblast processes that promote bone formation, whereas transforming growth factor–β1 (TGF-β1), which is locally produced, inhibits osteoblast differentiation (see Atfi and Baron). Binding of PTH to its G protein–coupled receptor (PTH1R) activates protein kinase A (PKA) and protein kinase C (PKC) signaling. Termination of PTH signaling occurs with internalization of PTH1R, a process that requires β-arrestins. The receptor complex for TGF-β1 is a heterodimer consisting of TβRI and TβRII; the latter is a serine-threonine kinase, and TGF-β1 signaling causes TβRII-mediated phosphorylation of Smad proteins, which then translocate to the nucleus and activate gene transcription. Using imaging and coimmunoprecipitation techniques, Qiu et al. found that treatment of transfected cells with PTH induced association of TβRII with PTH1R and endocytosis of this complex, as well as colocalization of β-arrestin2 with TβRII. PTH-induced interaction between TβRII and PTH1R also occurred in primary calvarial osteoblasts. PTH suppressed TGF-β signaling as assessed by phosphorylation of Smad2, nuclear translocation of Smad2/3, and a gene reporter assay; these effects required β-arrestin2 and the kinase activity of TβRII. TβRII phosphorylated PTH1R in a cluster of serine-threonine residues located between positions 484 and 498, and mutation of these residues resulted in a PTH1R mutant with reduced ability to interact with TβRII and inhibit TGF-β signaling. Primary osteoblasts from mice with an osteoblast-specific deletion of TβRII showed increased surface abundance of PTH1R and increased PTH signaling; the latter was determined by analysis of PKA signaling (increased basal cAMP concentrations and CREB phosphorylation). Mice with osteoblastic deficiency of TβRII showed increased bone formation (as assessed by analysis of multiple parameters, including bone mass and trabecular bone volume) and greater numbers of osteoclasts and osteoblasts in trabeculae compared with wild-type mice, and the skeletal defects of the TβRII–/– mice resembled those of mice with osteoblast-specific expression of a constitutively active PTH1R. Conversely, bone defects in TβRII–/– mice were rescued by injection of a PTH antagonist or partial ablation of PTH1R. Thus, by promoting internalization of PTH1R and TβRII, PTH terminates both its own signaling and that of TGF-β.
T. Qiu, X. Wu, F. Zhang, T. L. Clemens, M. Wan, X. Cao, TGF-β type II receptor phosphorylates PTH receptor to integrate bone remodelling signalling. Nat. Cell Biol. 12, 224–234 (2010). [PubMed]
A. Atfi, R. Baron, PTH battles TGF-β in bone. Nat. Cell Biol. 12, 205–207 (2010). [PubMed]