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Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion.

ABSTRACT: Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion. Macrophage colony stimulating factor (M-CSF) is abundant in rheumatoid arthritis (RA). However, the role of M-CSF in arthritic bone erosion is not completely understood. Here, we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS, a receptor for M-CSF, leading to the generation of FMS intracellular domain (FICD) fragments. Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses. Moreover, myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model. The FICD formed a complex with DAP5, and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATc1 protein expression. Moreover, targeting the MNK1/2 pathway diminished arthritic bone erosion. These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.

SUBMITTER: Mun SH

PROVIDER: S-EPMC8528869 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion.

Mun Se Hwan SH Bae Seyeon S Zeng Steven S Oh Brian B Chai Carmen C Kim Matthew Jundong MJ Kim Haemin H Kalliolias George G Dahia Chitra Lekha CL Oh Younseo Y Kim Tae-Hwan TH Ji Jong Dae JD Park-Min Kyung-Hyun KH

Bone research 20211020 1

Osteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion. Macrophage colony stimulating factor (M-CSF) is abundant in rheumatoid arthritis (RA). However, the role of M-CSF in arthritic bone erosion is not completely understood. Here, we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS, a receptor for M-CSF, leading to the generation of FMS intracellular domain (FICD) fragments. Increased lev ...[more]

PMID: 34671034

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Project description:Osteoclast differentiation and activity are controlled by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor-κB ligand (RANKL). Rab11A GTPase, belonging to Rab11 subfamily representing the largest branch of Ras superfamily of small GTPases, has been identified as one of the crucial regulators of cell surface receptor recycling. Nevertheless, the regulatory role of Rab11A in osteoclast differentiation has been completely unknown. In this study, we found that Rab11A was strongly upregulated at a late stage of osteoclast differentiation derived from bone marrow-derived macrophages (BMMs) or RAW-D murine osteoclast precursor cells. Rab11A silencing promoted osteoclast formation and significantly increased the surface levels of c-fms and receptor activator of nuclear factor-κB (RANK) while its overexpression attenuated osteoclast formation and the surface levels of c-fms and RANK. Using immunocytochemical staining for tracking Rab11A vesicular localization, we observed that Rab11A was localized in early and late endosomes, but not lysosomes. Intriguingly, Rab11A overexpression caused the enhancement of fluorescent intensity and size-based enlargement of early endosomes. Besides, Rab11A overexpression promoted lysosomal activity via elevating the endogenous levels of a specific lysosomal protein, LAMP1, and two key lysosomal enzymes, cathepsins B and D in osteoclasts. More importantly, inhibition of the lysosomal activity by chloroquine, we found that the endogenous levels of c-fms and RANK proteins were enhanced in osteoclasts. From these observations, we suggest a novel function of Rab11A as a negative regulator of osteoclastogenesis mainly through (i) abolishing the surface abundance of c-fms and RANK receptors, and (ii) upregulating lysosomal activity, subsequently augmenting the degradation of c-fms and RANK receptors, probably via the axis of early endosomes-late endosomes-lysosomes in osteoclasts.

Project description:BackgroundBone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC.MethodsWe comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed.ResultsA total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16).ConclusionsGDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

Dataset Information

Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion.

Publications

Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion.

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