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1.
Bone Res ; 12(1): 29, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38744829

RESUMEN

Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.


Asunto(s)
Endosomas , Lisosomas , Osteoclastos , Animales , Osteoclastos/metabolismo , Lisosomas/metabolismo , Endosomas/metabolismo , Ratones , Ratones Noqueados , Resorción Ósea/metabolismo , Resorción Ósea/patología , Resorción Ósea/genética , Transporte de Proteínas , Ratones Endogámicos C57BL , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab/genética , Diferenciación Celular , Eliminación de Gen , Catepsina K/metabolismo , Catepsina K/genética , Femenino , Proteínas de Unión a GTP rab7
2.
Nat Commun ; 15(1): 1024, 2024 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-38310093

RESUMEN

Osteoarthritis (OA) is a progressive and irreversible degenerative joint disease that is characterized by cartilage destruction, osteophyte formation, subchondral bone remodeling, and synovitis. Despite affecting millions of patients, effective and safe disease-modifying osteoarthritis drugs are lacking. Here we reveal an unexpected role for the small molecule 5-aminosalicylic acid (5-ASA), which is used as an anti-inflammatory drug in ulcerative colitis. We show that 5-ASA competes with extracellular-matrix collagen-II to bind to osteoclast-associated receptor (OSCAR) on chondrocytes. Intra-articular 5-ASA injections ameliorate OA generated by surgery-induced medial-meniscus destabilization in male mice. Significantly, this effect is also observed when 5-ASA was administered well after OA onset. Moreover, mice with DMM-induced OA that are treated with 5-ASA at weeks 8-11 and sacrificed at week 12 have thicker cartilage than untreated mice that were sacrificed at week 8. Mechanistically, 5-ASA reverses OSCAR-mediated transcriptional repression of PPARγ in articular chondrocytes, thereby suppressing COX-2-related inflammation. It also improves chondrogenesis, strongly downregulates ECM catabolism, and promotes ECM anabolism. Our results suggest that 5-ASA could serve as a DMOAD.


Asunto(s)
Cartílago Articular , Osteoartritis , Humanos , Masculino , Animales , Ratones , Mesalamina/farmacología , Mesalamina/uso terapéutico , PPAR gamma/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Cartílago Articular/metabolismo , Condrocitos/metabolismo , Modelos Animales de Enfermedad
3.
Exp Mol Med ; 54(6): 825-833, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35760874

RESUMEN

Branched-chain aminotransferase 1 (BCAT1) transfers the amine group on branched-chain amino acids (BCAAs) to alpha-ketoglutarate. This generates glutamate along with alpha-keto acids that are eventually oxidized to provide the cell with energy. BCAT1 thus plays a critical role in sustaining BCAA concentrations and availability as an energy source. Osteoclasts have high metabolic needs during differentiation. When we assessed the levels of amino acids in bone marrow macrophages (BMMs) that were undergoing receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation, we found that the BCAA levels steadily increase during this process. In vitro analyses then showed that all three BCAAs but especially valine were needed for osteoclast maturation. Moreover, selective inhibition of BCAT1 with gabapentin significantly reduced osteoclast maturation. Expression of enzymatically dead BCAT1 also abrogated osteoclast maturation. Importantly, gabapentin inhibited lipopolysaccharide (LPS)-induced bone loss of calvaria in mice. These findings suggest that BCAT1 could serve as a therapeutic target that dampens osteoclast formation.


Asunto(s)
Aminoácidos de Cadena Ramificada , Osteoclastos , Transaminasas/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Animales , Diferenciación Celular , Gabapentina/farmacología , Ratones , Osteoclastos/metabolismo , Ligando RANK/metabolismo
4.
J Cell Physiol ; 237(1): 846-855, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34407208

RESUMEN

Actin rings are unique structures that facilitate the attachment of osteoclasts to the bone matrix during bone resorption. Previous studies have shown that tetraspanin7 (TSPAN7) plays an important role in the reorganization of the cytoskeleton necessary for the bone-resorbing activity of osteoclasts. However, questions remain as to the mechanisms by which TSPAN7 regulates this cytoskeletal rearrangement. In this study, we investigated the roles of TSPAN7 in osteoclasts by deleting the Tm4sf2 gene in mice, which encodes TSPAN7. The Tm4sf2 global knockout model showed protective effects on pathological bone loss, but no discernible changes in bone phenotypes under physiological conditions. In vitro study revealed that ablation of Tm4sf2 caused significant defects in integrin-mediated actin ring formation, thereby leading to significantly decreased bone resorption. Additionally, we demonstrated an association between TSPAN7 and the receptor activator of nuclear factor-кB/αvß3 integrin. Overall, our findings suggest that TSPAN7 acts as a novel modulator regulating the bone-resorbing function of osteoclasts.


Asunto(s)
Resorción Ósea , Osteoclastos , Actinas , Animales , Resorción Ósea/patología , Diferenciación Celular , Integrina alfaVbeta3/genética , Integrinas/genética , Proteínas de la Membrana , Ratones , Proteínas del Tejido Nervioso , Osteoclastos/patología , Ligando RANK/genética , Tetraspaninas/genética
5.
FASEB J ; 34(9): 12894-12906, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32741026

RESUMEN

Osteoclast-mediated inflammatory bone resorption is a major cause of many inflammatory bone disorders, including rheumatoid arthritis and periodontitis. However, the mechanisms regulating osteoclast differentiation in inflammatory settings are not well understood. We demonstrate here that early estrogen-induced gene 1 (EEIG1)-deficient mice are protected from inflammatory bone loss as determined with the use of models of lipopolysaccharide (LPS)-induced bone destruction. EEIG1-deficient macrophages markedly decreased RANKL- and TNFα-mediated osteoclastogenesis due to the downregulation of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which is an essential transcription factor for osteoclast formation. In contrast, expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor that blocks osteoclast differentiation, is elevated in EEIG1-deficient macrophages relative to wild-type cells. We found that reduced expression of B lymphocyte-induced maturation protein-1 (Blimp1) by siRNA downregulated RANKL-induced EEIG1 levels, whereas overexpression of Blimp1 potentiated EEIG1 levels. Mechanistic studies revealed that EEIG1 forms a complex with Blimp1 to negatively regulate the expression of the anti-osteoclastogenic gene, Irf8. We elucidated a novel mechanism by which EEIG1 restricts IRF8 expression and function, thereby enhancing the osteoclast formation by contributing to Blimp1-mediated IRF8 regulation. Together, these findings identify EEIG1 as a key regulator of osteoclastogenesis and a possible therapeutic target for pathological bone destruction.


Asunto(s)
Resorción Ósea/metabolismo , Factores Reguladores del Interferón/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Animales , Resorción Ósea/patología , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Osteoclastos/patología
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