Conclusions and perspectives - Transduction pathways implicated in osteoblastic cells activatio

Stimulation of Type 1 parathyroid hormone receptor (PTH1R) mediates activation of multiple signaling pathways. As a paradigm, PTH-stimulated cAMP/PKA and IP3/Ca²⁺ signaling in kidney and bone is essential for its effects on serum calcium homeostasis and bone turnover, whereas MAPK signaling in osteoblasts may play an important role on osteoblastic proliferation and differentiation and thus on bone formation (128, 191, 205, 214). Cytoplasmic molecules such as -arrestin that interact with both PTH1R and multiple signaling effectors have been shown to regulate G proteins coupling/uncoupling and PTH1R fate/trafficking (245, 248, 251). In addition, -arrestin knock out mice have decreased bone mass and have an altered response to PTH anabolic stimulus on trabecular bone and an improved cortical response to anabolic PTH (249, 253). Our work now bridges these in vitro and in vivo findings by showing that -arrestin also mediates PTH-stimulated activation of MAPK ERK1/2 through c-Src and in turn that MAPKs activation is important for osteoblastic differentiation.

This discussion will now focus on the analysis and understanding of the somewhat divergent results obtained in HEK293 and osteoblastic cells.

First concerning PTH-induced MAPKs activation, both ERK1/2 and p38 were stimulated in osteoblastic (MC4) cells whereas in HEK293 cells and primary osteoblastic cells only ERK1/2 was activated. The activation profile was also different with a delayed activation of about one hour in MC4 cells and in contrary very rapid (after 5 min.) and transient in HEK293 cells. Consistent with our findings in HEK293 cells and primary osteoblastic cells, another study using osteoblastic (MC4) cells found that PTH-induced ERK1/2 activation was rapid (peak at 5 min) (129). In that study, however, ERK1/2 activation by PTH was apparently cAMP-dependent. In our hands, on another side, p38 activation in MC4 cells was cAMP/PKA-dependent (and delayed until 1 hour), whereas ERK1/2 activation was not. These differences could partly be explained by the presence or absence of B-Raf in MC4 cells and HEK293 cells respectively (129, 293). Moreover, the experimental conditions slightly differed [time of culture for MC4 cells was shorter (3-4 days) compared to ours (8-9 days)], suggesting that PTH1R-mediated signaling pathways

may be dependent on the cell type, duration and conditions of culture. Thus, in our culture conditions the delayed activation in MC4 cells could be explained by an indirect mechanism such as for instance an inhibition of phosphatase(s). The relevance of these findings with regard to physiological and pathophysiological processes in vivo should therefore be taken with caution. At best, these experiments show the potentiality of PTH and PTH1R to activate multiple signaling pathways, without necessarily indicating that theses events all occur in every tissue and/or conditions where the receptor is expressed.

Molecular mechanisms of ERK1/2 activation by various GPCRs have been extensively studied. In general, each GPCR is able to activate ERK1/2 through a variety of signaling pathways. Second messengers between the receptor and ERK1/2 are often similar, but their activation mechanisms and interactions with other molecules differ from each other. For example, c-Src is implicated in 2-adrenergic receptor (AR)-mediated ERK1/2 activation by binding to -arrestin (235), whereas c-Src directly binds to the 3-AR to induce ERK1/2 activation (228). It appears difficult therefore to predict the mechanisms of MAPKs activation through GPCRs based solely on their structural homology. In HEK293 cells we found that PTH-induced ERK1/2 activation was Gq/PKC-dependent, as also described in rat osteoblastic cells and opossum kidney cells (128, 206). Of note, in HEK293 cells B-Raf is absent (293), precluding direct activation by cAMP/PKA pathway and potentially explaining the predominant implication of Gq/PKC signaling for ERK1/2 activation in these cells (see figure 10 to see the signaling pathways). It is not described if B-Raf is present or absent in rat osteoblastic and opossum kidney cells (128, 206). On another side it has been shown that the Gq/PKC signaling pathway is implicated in PTH1R phosphorylation, subsequent -arrestin recruitment and PTH1R internalization (245).

Hence, in addition to directly activate ERK1/2, the Gq/PKC signaling pathway may trigger the cross talk between G proteins activation and -arrestin-dependent activation of ERK1/2.

In this study, we show more precisely that activation of Gq induces ERK1/2 phosphorylation by two different molecular mechanisms, one via the classical activation cascade of q-(PLC-/PKC/Raf1/MEK)-ERK1/2 and the other through the activation cascade of /c-Src-(Ras/Raf1/MEK)-ERK1/2 (see Figure 10). This latter shows the essential role of c-Src in ERK1/2 activation but also in stabilization of PTH1R internalization. Hence, activated c-Src binds to the PxxP motifs of PTH1R cytoplasmic tail through its SH3 domains and to -arrestin probably via its SH1 domain. Moreover, activation of transcription induced by this molecular complex shows that activated ERK1/2 migrate into the nucleus and does not only phosphorylate cytosolic substrates as generally described for GPCRs (234). Hence, ERK1/2 activation by Gq appears to be a general mechanism by which many GPCRs signals could eventually stimulate ERK1/2-dependent transcription. In contrast, the pathway involving the scaffolding of -arrestin2/c-Src/ to PTH1R polyproline motifs (PxxP) is quite unique to this receptor so far. Importantly, such mechanisms will target the signaling response towards its specific stimulus, in this case PTH.

Such targeting mechanisms could be crucial to determine the function of intracellular MAPK signaling. For instance, osteoblasts express both PTH1R and 2-adrenergic receptors (2-AR), yet stimulation by their respective agonists, PTH and noradrenalin (NA), has opposite effects on osteoblast functions (stimulation and inhibition of bone formation respectively) (71, 72, 94). Coupling the ERK1/2 activation cascade directly to the stimulated receptor could therefore copy the cellular response to its specific stimulus.

The purpose of using MC4 cells was to study molecular mechanisms of PTH-induced osteoblastic differentiation and mineralization. Here we confirm that PTH-stimulated cAMP is an important pathway to increase ALP activity and osteocalcin production (135-137, 195) which are both important for osteoblastic differentiation and mineralization. The pathway towards PTH-induced ALP activity was shown to be dependent on a definite signaling cascade beginning with cAMP production, then PKA and p38 activation, whereas for osteocalcin production, we showed that it was

dependent of cAMP, PKA and ERK1/2 without observing a definite activation cascade between these three molecules.

In these cells, we also show that PTH-induced p38 and ERK1/2 activation were delayed. This delayed activation could also be explained by an indirect mechanism such as for instance an inhibition of phosphatase(s). In fact, this response is different compared with a previous report in the same cells in which PTH induced a rapid activation of ERK1/2 that was found to be cAMP/B-Raf-dependent (129). The difference between our and this previous report is probably related to variation in culture conditions used to analyze PTH signaling. In the previous study, PTH was investigated in cells cultured for 3-4 days whereas in our analysis, PTH was added on cells cultured for 8-10 days. Thus, it seems that signaling pathways activated by PTH are dependent on the stage of differentiation.

Moreover, in our culture conditions, we observed that the basal activation of p38 increases with culture duration and it seems that PTH is able to induce its phosphorylation only during the differentiation phase and not during the proliferative phase. Therefore, p38 activation seems to be important to induce osteoblastic differentiation and PTH is able to increase its activity.

As a perspective and to investigate the relevance of the molecular mechanisms identified in vitro, the next step would be to test in vivo specific MAPKs inhibitors in mice treated with PTH and, in order to be more specific, to create an inducible knock out mice for p38 and ERK1/2 (tetracycline-on/-off system). These experiments would allow to investigate the role of MAPKs in PTH anabolic effects on bone.

Moreover to further elucidate the role of -arrestin in mediating PTH effects on bone, our group is currently developing osteoblasts targeted -arrestin1 and -arrestin2 knock out mice. All these models could be used to compare intermittent versus continuous PTH treatment in order to further delineate the role of -arrestin in PTH1R-mediated signaling and responses at the tissue level.

From our work, we can conclude that PTH has the property to activate multiple signaling pathways. This may therefore explain why, depending on the cell type and

localization in vivo, PTH may exert different, and sometimes opposite effects at the cellular level. Studies on shorter PTH analogs have depicted precise regions responsible for cAMP activation (aa 1-3), PKC stimulation (aa 29-32), and calcium mobilization (aa 3-7) (179, 180). Gardella et al. have shown that PTH analogs of only 11 or 14 amino acids are sufficient to activate PTH1R (294). Considering the complex receptor conformational changes required to bind -arrestin (295), it is however likely that very short PTH analogues have potential limitations with regard to triggering other signalling pathways, i.e. MAPKs. Our studies delineating the molecular mechanisms of PTH activity also show the complexity and intrications of PTH1Rc-mediated signaling pathways. Therefore, PTH appears to be more than a one-shot molecule and its effects on bone, as used for osteoporosis treatment, may encompass the variety of molecular events described here.

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