Fibronectin inhibits osteoclastogenesis while enhancing osteoclast activity via nitric oxide and interleukin‐1β‐mediated signaling pathways

Gramoun, Azza; Azizi, Natoosha; Sodek, Jaro; Heersche, J. N. M.; Nakchbandi, Inaam A.; Manolson, Morris F.

doi:10.1002/jcb.22791

Cited by 24 publications

(21 citation statements)

References 84 publications

(97 reference statements)

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“…Integrin β3 protein was not identified, and mRNA encoding integrin β3 was found to be unchanged during differentiation. Integrin α5β1 is involved in recognizing fibronectin, a bone matrix protein ( 56 ), and although the expression of integrin α5 mRNA and protein increased in the IOs and OCs, protein expression of integrin β1 was down-regulated, and mRNA of β1 was unchanged in these cells. In general, the expression of integrin α chain showed good correlation between mRNA and protein, but that of integrin β chain did not.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Functional Reprogramming during Osteoclast Development Using Quantitative Proteomics and mRNA Profiling

Narayanan

Manes

et al. 2014

Molecular & Cellular Proteomics

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In addition to forming macrophages and dendritic cells, monocytes in adult peripheral blood retain the ability to develop into osteoclasts, mature bone-resorbing cells. The extensive morphological and functional transformations that occur during osteoclast differentiation require substantial reprogramming of gene and protein expression. Here we employ -omic-scale technologies to examine in detail the molecular changes at discrete developmental stages in this process (precursor cells, intermediate osteoclasts, and multinuclear osteoclasts), quantitatively comparing their transcriptomes and proteomes. The data have been deposited to the ProteomeXchange with identifier PXD000471.Our analysis identified mitochondrial changes, along with several alterations in signaling pathways, as central to the development of mature osteoclasts, while also confirming changes in pathways previously implicated in osteoclast biology. In particular, changes in the expression of proteins involved in metabolism and redirection of energy flow from basic cellular function toward bone resorption appeared to play a key role in the switch from monocytic immune system function to specialized bone-turnover function. These findings provide new insight into the differentiation program involved in the generation of functional osteoclasts.

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Section: Resultsmentioning

confidence: 99%

Characterization of Functional Reprogramming during Osteoclast Development Using Quantitative Proteomics and mRNA Profiling

Narayanan

Manes

et al. 2014

Molecular & Cellular Proteomics

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“…It is worth noting that while the ECM proteins FN and VN decreased the number of osteoclast formed by ∼ 65%, OPN promoted osteoclast formation. Although the ECM proteins modulated osteoclast formation, none of these proteins affected RAW cell viability [Gramoun et al, in preparation].…”

Section: Resultsmentioning

confidence: 99%

Bone matrix proteins and extracellular acidification: Potential co‐regulators of osteoclast morphology

Gramoun¹,

Goto²,

Nordström³

et al. 2010

J of Cellular Biochemistry

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Osteoclasts are signaled by the bone matrix proteins fibronectin (FN), vitronectin (VN), and osteopontin (OPN) via integrins. To perform their resorptive function, osteoclasts cycle between compact (polarized), spread (non-resorbing) and migratory morphologies. Here we investigate the effects of matrix proteins on osteoclast morphology and how those effects are mediated using RAW 264.7 cells differentiated into osteoclasts on FN, VN, and OPN-coated culture dishes. After 96 h, 80% of osteoclasts on FN were compact while 25% and 16% on VN were in compact and migratory states respectively. In contrast, OPN induced osteoclast spreading. Furthermore, osteoclasts formed on VN and FN were two- to fourfold smaller than those formed on OPN in the 21-30 nuclei/osteoclast group. These effects were not due to defects in cytoskeletal reorganization of osteoclasts on VN and FN, demonstrated by the ability of these cells to spread in response to 35 ng/ml macrophage colony stimulating factor (M-CSF). Conversely, osteoclasts on OPN failed to spread when induced by M-CSF. Moreover, the extracellular pH on FN and VN (7.25 and 7.3, respectively) was significantly lower than that on OPN (∼7.4). We further investigated the role of extracellular pH and found that at pH 7.5 the duration of an osteoclast's compact phase was 25.6 min and that of the spread phase was 62.5 min. Reducing the pH to 7.0 increased the frequency of osteoclast cycling by threefold. These results show that matrix proteins play a role in regulating osteoclast morphology, possibly via altering extracellular and intracellular pH.

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“…Previous literature has also shown that fibronectin inhibits osteoclast differentiation activity, but stimulates function through IL-1β and nitric oxide. 57 Interestingly, fibronectin has been found to bind CD44 through its heparin-binding domain. 58 It will be interesting to determine if CD44, Osteoactivin and fibronectin have any interaction or involvement in osteoclast differentiation and function.…”

Section: Discussionmentioning

confidence: 99%

Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling

et al. 2016

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Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteolysis in vivo. Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation.

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Fibronectin inhibits osteoclastogenesis while enhancing osteoclast activity via nitric oxide and interleukin‐1β‐mediated signaling pathways

Cited by 24 publications

References 84 publications

Characterization of Functional Reprogramming during Osteoclast Development Using Quantitative Proteomics and mRNA Profiling

Characterization of Functional Reprogramming during Osteoclast Development Using Quantitative Proteomics and mRNA Profiling

Bone matrix proteins and extracellular acidification: Potential co‐regulators of osteoclast morphology

Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling

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