BoneKEy-Osteovision | Commentary

Osteoblast signaling and bone anabolism



DOI:10.1138/2002046

Commentary on: Spurney RF, Flannery PJ, Garner SC, Athirakul K, Liu S, Guilak F, Quarles LD. Anabolic effects of a G protein-coupled receptor kinase inhibitor expressed in osteoblasts. J Clin Invest. 2002 May;109(10):1361-71.

G protein-coupled receptors (GPCRs), through activation of their cognate G proteins, control a diverse range of physiological processes. The signals that mediate these effects depend upon the specific GPCR and G protein and include cyclic AMP, intracellular calcium, protein kinase C, arachidonic acid metabolites, and several others. An important component of this regulatory system is the control of the temporal aspects of the signaling process. In particular, signaling initiated by the vast majority of GPCRs is self-limited, due to the propensity of the receptor to be desensitized when continuously exposed to agonist. The fundamental mechanism of desensitization appears to be similar across the superfamily of GPCRs (). When agonists bind to the receptor, G protein activation occurs, resulting in the dissociation of the G protein into its constituent α- and βγ-subunits. Both of these components may contribute to activation of effector molecules that generate second messenger products. In addition, specific GPCR kinases (GRKs) are recruited to the plasma membrane where they associate with the βγ-subunits and thereby gain access to the GPCR. Phosphorylation of the GPCR by the GRK promotes the binding of another protein—members of the arrestin family. Arrestin binding to the GPCR prevents the further activation of the G protein by the receptor, resulting in desensitization. Phosphorylation of the receptor and arrestin binding also promote the endocytosis of the receptor (), rendering it unavailable for activation by extracellular ligand.

Desensitization of bone and kidney cells to the actions of parathyroid hormone (PTH) in response to continuous exposure to the hormone has been recognized for many years. More recently, it has become evident that the G protein-coupled PTH receptor is phosphorylated on serine residues in the proximal portion of the receptor's cytoplasmic tail following PTH binding, a process that appears to be mediated by GRK2 (). PTH binding also promotes association of arrestin proteins with the PTH receptor, and this process is facilitated by receptor phosphorylation (). Moreover, expression of a dominant-negative form of GRK2 was found to attenuate desensitization of the PTH receptor in osteoblastic cells ().

The physiological importance of PTH receptor desensitization in vivo has not been extensively investigated. Recently, Spurney et al. () have reported the effects of targeted osteoblast expression of a dominant-negative GRK2 on bone resorption and formation in transgenic mice. The transgene, driven by the mouse osteocalcin promoter, encodes the C-terminal portion of GRK2 and is capable of binding to G protein βγ-subunits but lacks the kinase domain. It is presumed to competitively inhibit the recruitment of GRK2 following agonist binding, thereby attenuating desensitization of signaling. Calvaria isolated from the transgenic mice were shown to display enhanced adenylyl cyclase signaling in response to PTH, consistent with attenuation of PTH receptor desensitization. Baseline bone resorption was shown to be elevated somewhat in the transgenic mice, evidenced by increased urinary excretion of deoxypyridinoline and by an increased ratio of RANKL:OPG mRNA in calvarial bone. More strikingly, bone formation parameters were increased in the transgenic mice. Dynamic parameters of bone formation were greatly increased, as were trabecular bone volume and width, osteoblast number, and osteoid surface.

These results suggest that inhibition of GRK activity and thus inhibition of GPCR desensitization augments anabolic signaling in osteoblasts. These are potentially important findings, but a few caveats are in order. The mechanism underlying these effects of the GRK inhibitor is not necessarily through inhibition of GRK alone. This molecule binds G protein βγ-subunits and can thus inhibit activation of effectors that depend on these subunits (e.g., MAP kinase). Indeed, expression of a dominant-inhibitor of GRK2 was shown to attenuate cell proliferation and growth factor-stimulated MAP kinase activity in osteosarcoma cells (). In addition, there are many GPCRs in osteoblasts and multiple G proteins can be activated (). Many of these are targets of GRK2, and it is difficult to predict either the net effect of GRK2 inhibition on the signaling properties of the cells or the relationship between observed phenotypes and a particular signaling pathway.

Nonetheless, there are a number of interesting implications of these results. The findings lend some credence to the notion that continuous administration of high doses of PTH might fail to produce an anabolic response because of the sensitivity of the anabolic signaling pathway in osteoblasts to homologous desensitization. In this regard, it will be of interest to compare the anabolic responses of the transgenic mice vs. their wild-type littermates to continuously-administered PTH. As the transgene was driven by the osteocalcin promoter, these results demonstrate that altered signaling in mature osteoblasts can produce an anabolic response. A reasonable hypothesis is that the altered G protein signaling resulted in an inhibition of osteoblast apoptosis, an action thought to contribute to the anabolic response to PTH (). This idea needs to be tested directly. Further studies with these transgenic mice will doubtless shed new light on the nature of the signaling pathways in the osteoblast that lead to anabolic skeletal responses.


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