The role of osteoclastic bone resorption in the pathogenesis of osteoarthritis

This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.

Download Full-text

Rab3D Regulates a Novel Vesicular Trafficking Pathway That Is Required for Osteoclastic Bone Resorption

Molecular and Cellular Biology ◽

10.1128/mcb.25.12.5253-5269.2005 ◽

2005 ◽

Vol 25 (12) ◽

pp. 5253-5269 ◽

Cited By ~ 57

Author(s):

Nathan J. Pavlos ◽

Jiake Xu ◽

Dietmar Riedel ◽

Joyce S. G. Yeoh ◽

Steven L. Teitelbaum ◽

...

Keyword(s):

Bone Resorption ◽

Vesicular Trafficking ◽

Osteoclastic Bone Resorption ◽

Wild Type ◽

Trafficking Pathway ◽

Golgi Network ◽

Deficient Mice ◽

Constitutively Active

ABSTRACT Rab3 proteins are a subfamily of GTPases, known to mediate membrane transport in eukaryotic cells and play a role in exocytosis. Our data indicate that Rab3D is the major Rab3 species expressed in osteoclasts. To investigate the role of Rab3D in osteoclast physiology we examined the skeletal architecture of Rab3D-deficient mice and found an osteosclerotic phenotype. Although basal osteoclast number in null animals is normal the total eroded surface is significantly reduced, suggesting that the resorptive defect is due to attenuated osteoclast activity. Consistent with this hypothesis, ultrastructural analysis reveals that Rab3D−/− osteoclasts exhibit irregular ruffled borders. Furthermore, while overexpression of wild-type, constitutively active, or prenylation-deficient Rab3D has no significant effects, overexpression of GTP-binding-deficient Rab3D impairs bone resorption in vitro. Finally, subcellular localization studies reveal that, unlike wild-type or constitutively active Rab3D, which associate with a nonendosomal/lysosomal subset of post-trans-Golgi network (TGN) vesicles, inactive Rab3D localizes to the TGN and inhibits biogenesis of Rab3D-bearing vesicles. Collectively, our data suggest that Rab3D modulates a post-TGN trafficking step that is required for osteoclastic bone resorption.

Download Full-text

The Role of Cyclic AMP, Calcium, and Prostaglandins in the Induction of Osteoclastic Bone Resorption Associated with Experimental Tooth Movement

Journal of Dental Research ◽

10.1177/00220345830620080501 ◽

1983 ◽

Vol 62 (8) ◽

pp. 877-881 ◽

Cited By ~ 53

Author(s):

K. Yamasaki

Keyword(s):

Bone Resorption ◽

Cyclic Amp ◽

Tooth Movement ◽

Osteoclastic Bone Resorption ◽

Experimental Tooth Movement

Download Full-text

Role of Bone Mineral and Organic Matrix in Induction of Osteoclastic Bone Resorption.

Nihon Hotetsu Shika Gakkai Zasshi ◽

10.2186/jjps.36.1148 ◽

1992 ◽

Vol 36 (5) ◽

pp. 1148-1161

Author(s):

Mikio Takeuchi

Keyword(s):

Bone Resorption ◽

Bone Mineral ◽

Organic Matrix ◽

Osteoclastic Bone Resorption

Download Full-text

Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22094717 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4717

Author(s):

Jin-Young Lee ◽

Da-Ae Kim ◽

Eun-Young Kim ◽

Eun-Ju Chang ◽

So-Jeong Park ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Map Kinases ◽

Osteoclast Differentiation ◽

Dependent Manner ◽

Dual Action ◽

Dose Dependent ◽

Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

Download Full-text