Abstract
The Osteocyte, recognized as a major orchestrator of osteoblast and osteoclast activity, is the most important key player during bone remodeling processes. Imbalances occurring during bone remodeling, caused by hormone perturbations or by mechanical loading alterations, can induce bone pathologies such as osteoporosis. Recently, the active fraction of parathormone, PTH (1-34) or Teriparatide (TPTD), was chosen as election treatment for osteoporosis. The effect of such therapy is dependent on the temporal manner of administration. The molecular reasons why the type of administration regimen is so critical for the fate of bone remodeling are numerous and not yet well known. Our study attempts to analyze diverse signaling pathways directly activated in osteocytes upon TPTD treatment. By means of gene array analysis, we found many molecules upregulated or downregulated in osteocytes. Later, we paid attention to Wisp-2, a protein involved in the Wnt pathway, that is secreted by MLO-Y4 cells and increases upon TPTD treatment and that is able to positively influence the early phases of osteogenic differentiation. We also confirmed the pro osteogenic property of Wisp-2 during mesenchymal stem cell differentiation into the preliminary osteoblast phenotype. The same results were confirmed with an in vivo approach confirming a remarkable Wisp-2 expression in metaphyseal trabecular bone. These results highlighted the anabolic roles unrolled by osteocytes in controlling the action of neighboring cells, suggesting that the perturbation of certain signaling cascades, such as the Wnt pathway, is crucial for the positive regulation of bone formation.
Highlights
The bone tissue is a dynamic tissue that constantly undergoes modifications in response to physiological and pathological alterations (Hadjidakis and Androulakis, 2006; Raggatt and Partridge, 2010; Sims and Walsh, 2012), through bone remodeling
It is well known that osteocytes are a source of osteoprotegerin, the potent inhibitor of RANKL, that mediates the inhibition of bone resorption, but they are the producers of Sclerostin, the most important anti-anabolic regulator of bone formation by osteoblasts (Pietrzyk et al, 2017; Tatsumi et al, 2007; Weinstein et al, 2011; Xiong et al, 2014)
In order to select the concentration of TPTD that did not affect cell viability, Murine Long bone Osteocyte Y4 (MLO-Y4) were cultured for 24 h and treated for 6, 9 and 12 h with two different drug concentrations, 10 nM and 1 μM, respectively
Summary
The bone tissue is a dynamic tissue that constantly undergoes modifications in response to physiological and pathological alterations (Hadjidakis and Androulakis, 2006; Raggatt and Partridge, 2010; Sims and Walsh, 2012), through bone remodeling (i.e. coupled bone resorption and bone formation). It is interesting and not well investigated Wisp-2, that is a member of the Wnt inducible signaling pathway protein subfamily, which belongs to the connective tissue growth factor (CTGF) family It may play an important role in modulating bone turnover; in particular, it: 1) promotes the adhesion of osteoblast cells, 2) inhibits the binding of fibrinogen to integrin receptors and 3) inhibits osteocalcin production. Our data indicate the osteocytes as producers of Wisp-2, as a molecule with a great osteogenic power able to modulate the activity of the neighboring cells, such as osteoblast or bone lining cells Through this mechanism, we focus our attention on one of the possible ways by which the osteocytes may regulate the differentiation of mineralized tissues when exposed to TPTD, thereby emphasizing one of the possible important functional roles that this cell type has in bone remodeling and, more generally, in skeletal metabolism
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