Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis

Frattini, Annalisa; Orchard, Paul J.; Sobacchi, Cristina; Giliani, Silvia; Abinun, Mario; Mattsson, Jan P.; Keeling, David J.; Andersson, Ann Katrin; Wallbrandt, Pia; Zecca, Luigi; Notarangelo, Luigi D.; Vezzoni, Paolo; Villa, Anna

doi:10.1038/77131

Cited by 625 publications

(456 citation statements)

References 19 publications

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“…V-ATPases are proton-translocating transporters that become enriched in ruffled borders of polarized osteoclasts and mediate acidification of the resorptive space [24,25]. A lack of V-ATPases in the ruffled border results in impaired bone resorption, and in humans and mouse models, a malignant form of osteopetrosis [26][27][28][29]. Figure 5B shows confocal sections at the base of either a control-transfected (top panels) or Tm-4 overexpressing (bottom panels) cell.…”

Section: Overexpression Of Tropomyosin 4 Results In Altered F-actin Smentioning

confidence: 99%

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

McMichael

Lee

2008

Experimental Cell Research

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Tropomyosins (Tms) are α-helical dimers that bind and stabilize actin microfilaments while regulating their accessibility to other actin-associated proteins. Four genes encode expression of over forty Tms, most of which are expressed in nonmuscle cells. In recent years, it has become clear that individual Tm isoforms may regulate specific actin pools within cells. In this study, we examined how osteoclast function may be regulated by the tropomyosin isoform Tm-4, which we previously showed to be highly localized to podosomes and sealing zones of osteoclasts. RNAi-mediated knockdown of Tm-4, both in RAW264.7-and mouse marrow-derived osteoclasts, resulted in thinning of the actin ring of the sealing zone. Knockdown of Tm-4 also resulted in diminished bone resorptive capacity and altered resorption pit shape. In contrast, osteoclasts overexpressing Tm-4 demonstrated thickened podosomes on glass as well as thickened, aberrant actin structures on bone, and diminished motility and resorptive capacity. These results indicate that Tm-4 plays a role in regulating adhesion structures of osteoclasts, most likely by stabilizing the actin microfilaments present in podosomes and the sealing zone.

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Section: Overexpression Of Tropomyosin 4 Results In Altered F-actin Smentioning

confidence: 99%

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

McMichael

Lee

2008

Experimental Cell Research

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“…Furthermore, mutations in the TCIRG1 gene, which encodes for the human a3 subunit, have been reported in patients affected by infantile malignant osteopetrosis, a heterogeneous autosomal recessive disorder of bone metabolism (12)(13)(14)(15). In addition, recent study has shown that V 0 subunit d2 is important for osteoclast fusion (37).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, mutations in the human TCIRG1 gene, which encodes for a osteoclast specific V-ATPase subunit, a3, results in infantile malignant osteopetrosis, thus substantiating the importance of V-ATPase in osteoclastic bone resorption (12)(13)(14)(15). The structural and functional analyses of the V-ATPase complex in osteoclasts might facilitate the development of anti-resorptive agents targeting specifically the osteoclast V-ATPases (16).…”

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confidence: 99%

Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone Resorption

Feng

Cheng

Pavlos

et al. 2008

Journal of Biological Chemistry

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Solubilization of mineralized bone by osteoclasts is largely dependent on the acidification of the extracellular resorption lacuna driven by the vacuolar (H؉)-ATPases (V-ATPases)polarized within the ruffled border membranes. V-ATPases consist of two functionally and structurally distinct domains, V 1 and V 0 . The peripheral cytoplasmically oriented V 1 domain drives ATP hydrolysis, which necessitates the translocation of protons across the integral membrane bound V 0 domain. Here, we demonstrate that an accessory subunit, Ac45, interacts with the V 0 domain and contributes to the vacuolar type proton pump-mediated function in osteoclasts. Consistent with its role in intracellular acidification, Ac45 was found to be localized to the ruffled border region of polarized resorbing osteoclasts and enriched in pH-dependent endosomal compartments that polarized to the ruffled border region of actively resorbing osteoclasts. Interestingly, truncation of the 26-amino acid residue cytoplasmic tail of Ac45, which encodes an autonomous internalization signal, was found to impair bone resorption in vitro. Furthermore, biochemical analysis revealed that although both wild type Ac45 and mutant were capable of associating with subunits a3, c, c؆, and d, deletion of the cytoplasmic tail altered its binding proximity with a3, c؆, and d. In all, our data suggest that the cytoplasmic terminus of Ac45 contains elements necessary for its proper interaction with V 0 domain and efficient osteoclastic bone resorption.Osteoclasts are terminally differentiated multinucleated cells derived from the hematopoietic lineage that specialize in the solubilization of mineralized bone material (1). Upon attachment to the bone surface, the osteoclast undergoes a series of cytoskeletal reorganization and polarization events that culminate in the formation of a unique apical membrane known as the ruffled border. The ruffled border is the "resorptive organelle" of the osteoclast and is formed by the polarized targeting and fusion of acidified intracellular vesicles with the plasma membrane (2-4). These transport vesicles courier acidifying machineries as well as osteolytic enzymes such as, TRACP, cathepsin K, and matrix metalloproteinases (2, 5-7) to the ruffled border membrane domain where each cargo plays a discrete role in the resorptive function. Vacuolar H ϩ -adenosine triphosphatases (V-ATPases) 5 that line the ruffled border have long been established to play a vital role in the resorptive process. V-ATPases function to pump H ϩ into the underlying resorptive lacunae. This elevation in protons results in a highly acidified microenvironment that solubilizes the mineralized component of bone while providing optimal conditions for the degradation of the exposed organic phase by collagenolytic enzymes such cathepsin K (2, 7).The importance of V-ATPase in osteoclastic bone resorption is exemplified by studies employing specific inhibitors and gene knock-out strategies to impair V-ATPase functions (8 -11). Furthermore, mutations in the human TCIRG1 g...

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“…Cross-linked bone collagen and the peptides containing cross-links used to estimate the rate of bone resorption in serum or urine are not degraded by proteinases. A mutation in the Atp6i also causes an osteopetrosis in human [17,18].…”

Section: Osteoclast Physiologymentioning

confidence: 99%

Molecular Understanding of Osteoclast Differentiation and Physiology

Lee

2010

Endocrinol Metab

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Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis

Cited by 625 publications

References 19 publications

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone Resorption

Molecular Understanding of Osteoclast Differentiation and Physiology

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