Page 36 - Physico-Chemical Niche Conditions for Bone Cells

Physicochemical niche conditions and mechanosensing
Signaling molecules
Mechanosensitive osteocytes secrete several signaling molecules, i.e. nitric oxide (NO), prostaglandins, DMP1, PHEX, MEPE, FGF-23, BMPs, Wnts, osteonectin, osteocalcin, sclerostin, Lrp5, RANKL, etc. [66]. After mechanical loading, osteocytes alter signaling molecule production, thereby affecting bone formation activity by osteoblasts and/or bone resorption activity by osteoclasts, and these cell types could be considered to exist in a complex niche [66]. However, many of these molecules may also affect the behavior of osteocytes in an autocrine or paracrine fashion, as in a simple niche. In addition, mechanically loaded myoblasts increase NO production, hepatocyte growth factor (HGF) gene expression [67], and proliferation-related gene expression [68]. These effects are important during exercise, when myofibers undergo substantial length changes by passive or active stretching, resulting in the opening of calcium channels and activation of integrin signaling pathways [67].
The relationship between bone and muscle might not only be determined by mechanical behavior, but also by biochemical communication [69]. An overview of the details regarding cellular chemical signaling molecules is provided in Table 2.
Oxygen/metabolism
The oxygen tension is important for cell fate and function. It determines the oxidative metabolism and energy state. A low energy state (i.e. high ratio AMP/ATP) will activate adenosine monophosphate kinase (AMPK). Oxygen tension levels may be involved in the activation of hypoxia inducible factor 1a (HIF1a). At low oxygen level (i.e. hypoxia), HIF1a is not degraded and will regulate transcription of HIF1A- and/or HIF1B-responsive genes [70]. Activation of the HIFa signaling pathway in osteoblasts is important for osteogenesis and angiogenesis [71]. HIFa also regulates myoblast differentiation via activation of miR-210 transcription in myotubes [72]. Therefore, it is important to maintain intracellular oxygen homeostasis for bone and muscle cell function.
Hypoxia in environmental or clinical settings is potentially threatening tissue or organ oxygen homeostasis. In bone, hypoxia inhibits osteoblast growth and differentiation, and strongly promotes osteoclast formation [73]. It has not been totally resolved whether and how oxygen sensing affects the function of osteocytes that remain in a low oxygen microenvironment. Oxygen sensing by the oxygen sensor prolyl hydroxylase-2 (PHD2) in osteocytes has been shown to decrease bone mass through epigenetic regulation of sclerostin, and targeting PHD2 results in an osteo-anabolic response associated with reduced bone resorption [74]. Hypoxia is most likely the condition for the mature osteocytes and less so for the early, embedding osteocytes. In healthy bone, there is a persistent matrix and fluid-filled gap of 50-80 nm between the calcified matrix and the osteocyte cell membrane, which is of
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