The cell biology of osteoclast function

2000 ◽  
Vol 113 (3) ◽  
pp. 377-381 ◽  
Author(s):  
H.K. Vaananen ◽  
H. Zhao ◽  
M. Mulari ◽  
J.M. Halleen
Keyword(s):  
Bone Resorption ◽  
Cell Biology ◽  
Degradation Products ◽  
Bone Matrix ◽  
Organic Matrix ◽  
Endosomal Membrane ◽  
Multinucleated Cells ◽  
Sealing Zone ◽  
Ruffled Border ◽  
Osteoclast Function

Osteoclasts are multinucleated cells responsible for bone resorption. They have developed an efficient machinery for dissolving crystalline hydroxyapatite and degrading organic bone matrix rich in collagen fibers. When initiating bone resorption, osteoclasts become polarized, and three distinct membrane domains appear: a ruffled border, a sealing zone and a functional secretory domain. Simultaneously, the cytoskeleton undergoes extensive re-organisation. During this process, the actin cytoskeleton forms an attachment ring at the sealing zone, the membrane domain that anchors the resorbing cell to bone matrix. The ruffled border appears inside the sealing zone, and has several characteristics of late endosomal membrane. Extensive vesicle transport to the ruffled border delivers hydrochloric acid and proteases to an area between the ruffled border and the bone surface called the resorption lacuna. In this extracellular compartment, crystalline hydroxyapatite is dissolved by acid, and a mixture of proteases degrades the organic matrix. The degradation products of collagen and other matrix components are endocytosed, transported through the cell and exocytosed through a functional secretory domain. This transcytotic route allows osteoclasts to remove large amounts of matrix-degradation products without losing their tight attachment to underlying bone. It also facilitates further processing of the degradation products intracellularly during the passage through the cell.

Clear zone in osteoclast function: role of podosomes in regulation of bone-resorbing activity

1991 ◽  
Vol 261 (1) ◽  
pp. C1-C7 ◽  
Author(s):  
A. Teti ◽  
P. C. Marchisio ◽  
A. Z. Zallone
Keyword(s):  
Bone Resorption ◽  
Bone Matrix ◽  
Focal Adhesions ◽  
Cell Polarization ◽  
Free Calcium ◽  
Clear Zone ◽  
Discrete Structures ◽  
Free Calcium Concentration ◽  
Ruffled Border ◽  
Osteoclast Function

The adhesion of osteoclasts to the bone matrix is mandatory for bone resorption. Contact of the osteoclast with bone surface induces, in fact, cell polarization and organization of the resorbing apparatus, the so-called “ruffled border.” Cell-matrix interaction in osteoclasts is a complex phenomenon resulting from formation of the “clear zone,” a cytoplasmic area presenting the adhering plasma membrane, or “sealing membrane.” The sealing membrane surrounds the ruffled border and seals the resorbing compartment, namely the extracellular space in which bone resorption takes place. Adhesion at this level occurs via specialized discrete structures, the “podosomes.” Podosomes present most of the protein commonly found in focal adhesions, but with a peculiar organization. They are dynamic elements suitable for regulation, according with the functional demand of the cell. Their assembly increases during bone resorption and is regulated by the cytosolic free calcium concentration and the activity of protein kinase C.

scholarly journals The Mechanism Switching the Osteoclast From Short to Long Duration Bone Resorption

2021 ◽  
Vol 9 ◽  
Author(s):  
Jean-Marie Delaisse ◽  
Kent Søe ◽  
Thomas Levin Andersen ◽  
Aleksandra Maria Rojek ◽  
Niels Marcussen
Keyword(s):  
Bone Resorption ◽  
Bone Matrix ◽  
Bone Destruction ◽  
Leading Edge ◽  
Cavity Wall ◽  
Cell Phenotype ◽  
Bone Surface ◽  
Sealing Zone ◽  
Ruffled Border ◽  
And Migration

The current models of osteoclastic bone resorption focus on immobile osteoclasts sitting on the bone surface and drilling a pit into the bone matrix. It recently appeared that many osteoclasts also enlarge their pit by moving across the bone surface while resorbing. Drilling a pit thus represents only the start of a resorption event of much larger amplitude. This prolonged resorption activity significantly contributes to pathological bone destruction, but the mechanism whereby the osteoclast engages in this process does not have an answer within the standard bone resorption models. Herein, we review observations that lead to envision how prolonged resorption is possible through simultaneous resorption and migration. According to the standard pit model, the “sealing zone” which surrounds the ruffled border (i.e., the actual resorption apparatus), “anchors” the ruffled border against the bone surface to be resorbed. Herein, we highlight that continuation of resorption demands that the sealing zone “glides” inside the cavity. Thereby, the sealing zone emerges as the structure responsible for orienting and displacing the ruffled border, e.g., directing resorption against the cavity wall. Importantly, sealing zone displacement stringently requires thorough collagen removal from the cavity wall - which renders strong cathepsin K collagenolysis indispensable for engagement of osteoclasts in cavity-enlargement. Furthermore, the sealing zone is associated with generation of new ruffled border at the leading edge, thereby allowing the ruffled border to move ahead. The sealing zone and ruffled border displacements are coordinated with the migration of the cell body, shown to be under control of lamellipodia at the leading edge and of the release of resorption products at the rear. We propose that bone resorption demands more attention to osteoclastic models integrating resorption and migration activities into just one cell phenotype.

scholarly journals Membrane trafficking in osteoclasts and implications for osteoporosis

2019 ◽  
Vol 47 (2) ◽  
pp. 639-650 ◽  
Author(s):  
Pei Ying Ng ◽  
Amy Brigitte Patricia Ribet ◽  
Nathan John Pavlos
Keyword(s):  
Membrane Trafficking ◽  
Bone Matrix ◽  
Rab Gtpases ◽  
Sorting Nexin ◽  
Multinucleated Cells ◽  
Biological Studies ◽  
Endocytic Sorting ◽  
Molecular Machinery ◽  
Intracellular Organelles ◽  
Ruffled Border

Abstract Osteoclasts are large multinucleated cells exquisitely adapted to resorb bone matrix. Like other eukaryotes, osteoclasts possess an elaborate ensemble of intracellular organelles through which solutes, proteins and other macromolecules are trafficked to their target destinations via membrane-bound intermediaries. During bone resorption, membrane trafficking must be tightly regulated to sustain the structural and functional polarity of the osteoclasts’ membrane domains. Of these, the ruffled border (RB) is most characteristic, functioning as the osteoclasts' secretory apparatus. This highly convoluted organelle is classically considered to be formed by the targeted fusion of acidic vesicles with the bone-facing plasma membrane. Emerging findings disclose new evidence that the RB is far more complex than previously envisaged, possessing discrete subdomains that are serviced by several intersecting endocytic, secretory, transcytotic and autophagic pathways. Bone-resorbing osteoclasts therefore serve as a unique model system for studying polarized membrane trafficking. Recent advances in high-resolution microscopy together with the convergence of genetic and cell biological studies in humans and in mice have helped illuminate the major membrane trafficking pathways in osteoclasts and unmask the core molecular machinery that governs these distinct vesicle transport routes. Among these, small Rab GTPases, their binding partners and members of the endocytic sorting nexin family have emerged as critical regulators. This mini review summarizes our current understanding of membrane trafficking in osteoclasts, the key molecular participants, and discusses how these transport machinery may be exploited for the development of new therapies for metabolic disorders of bone-like osteoporosis.

scholarly journals Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border.

1985 ◽  
Vol 101 (6) ◽  
pp. 2210-2222 ◽  
Author(s):  
R Baron ◽  
L Neff ◽  
D Louvard ◽  
P J Courtoy
Keyword(s):  
Bone Resorption ◽  
Membrane Protein ◽  
Ammonium Chloride ◽  
Bone Matrix ◽  
Low Ph ◽  
Lysosomal Membrane ◽  
Cell Biol ◽  
Extracellular Compartment ◽  
Ruffled Border ◽  
Lysosomal Membrane Protein

The extracellular compartment where bone resorption occurs, between the osteoclast and bone matrix, is shown in this report to be actively acidified. The weak base acridine orange accumulates within this compartment but dissipates after incubation with ammonium chloride. Upon removal of ammonium chloride, the cells are able to rapidly reacidify this compartment. The highly convoluted plasma membrane of the osteoclast facing this acidic compartment (ruffled border) is shown to contain a 100-kD integral membrane protein otherwise present in limiting membranes of lysosomes and other related acidified organelles (Reggio, H., D. Bainton, E. Harms, E. Coudrier, and D. Louvard, 1984, J. Cell Biol., 99:1511-1526; Tougard, C., D. Louvard, R. Picart, and A. Tixier-Vidal, 1985, J. Cell Biol. 100:786-793). Antibodies recognizing this 100-kD lysosomal membrane protein cross-react with a proton-pump ATPase from pig gastric mucosae (Reggio, H., D. Bainton, E. Harms, E. Coudrier, and D. Louvard, 1984, J. Cell Biol., 99:1511-1526), therefore raising the possibility that it plays a role in the acidification of both intracellular organelles and extracellular compartments. Lysosomal enzymes are also directionally secreted by the osteoclast into the acidified extracellular compartment which can therefore be considered as the functional equivalent of a secondary lysosome with a low pH, acid hydrolases, the substrate, and a limiting membrane containing the 100-kD antigen.

scholarly journals Aesculetin Inhibits Osteoclastic Bone Resorption through Blocking Ruffled Border Formation and Lysosomal Trafficking

2020 ◽  
Vol 21 (22) ◽  
pp. 8581
Author(s):  
Woojin Na ◽  
Eun-Jung Lee ◽  
Min-Kyung Kang ◽  
Yun-Ho Kim ◽  
Dong Yeon Kim ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Matrix ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Small Gtpase ◽  
Raw 264.7 Cells ◽  
Pleckstrin Homology Domain ◽  
Αvβ3 Integrin ◽  
Lysosomal Trafficking ◽  
Ruffled Border

For the optimal resorption of mineralized bone matrix, osteoclasts require the generation of the ruffled border and acidic resorption lacuna through lysosomal trafficking and exocytosis. Coumarin-type aesculetin is a naturally occurring compound with anti-inflammatory and antibacterial effects. However, the direct effects of aesculetin on osteoclastogenesis remain to be elucidated. This study found that aesculetin inhibited osteoclast activation and bone resorption through blocking formation and exocytosis of lysosomes. Raw 264.7 cells were differentiated in the presence of 50 ng/mL receptor activator of nuclear factor-κB ligand (RANKL) and treated with 1–10 μM aesculetin. Differentiation, bone resorption, and lysosome biogenesis of osteoclasts were determined by tartrate-resistance acid phosphatase (TRAP) staining, bone resorption assay, Western blotting, immunocytochemical analysis, and LysoTracker staining. Aesculetin inhibited RANKL-induced formation of multinucleated osteoclasts with a reduction of TRAP activity. Micromolar aesculetin deterred the actin ring formation through inhibition of induction of αvβ3 integrin and Cdc42 but not cluster of differentiation 44 (CD44) in RANKL-exposed osteoclasts. Administering aesculetin to RANKL-exposed osteoclasts attenuated the induction of autophagy-related proteins, microtubule-associated protein light chain 3, and small GTPase Rab7, hampering the lysosomal trafficking onto ruffled border crucial for bone resorption. In addition, aesculetin curtailed cellular induction of Pleckstrin homology domain-containing protein family member 1 and lissencephaly-1 involved in lysosome positioning to microtubules involved in the lysosomal transport within mature osteoclasts. These results demonstrate that aesculetin retarded osteoclast differentiation and impaired lysosomal trafficking and exocytosis for the formation of the putative ruffled border. Therefore, aesculetin may be a potential osteoprotective agent targeting RANKL-induced osteoclastic born resorption for medicinal use.

Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone

1999 ◽  
Vol 112 (22) ◽  
pp. 3985-3993 ◽  
Author(s):  
I. Nakamura ◽  
M.F. Pilkington ◽  
P.T. Lakkakorpi ◽  
L. Lipfert ◽  
S.M. Sims ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Cell Attachment ◽  
Leading Edge ◽  
In Vivo Studies ◽  
Sealing Zone ◽  
Osteoclast Function ◽  
Alpha V Beta 3

The alpha(v)beta(3) integrin is abundantly expressed in osteoclasts and has been implicated in the regulation of osteoclast function, especially in cell attachment. However, in vivo studies have shown that echistatin, an RGD-containing disintegrin which binds to alpha(v)beta(3), inhibits bone resorption without changing the number of osteoclasts on the bone surface, suggesting inhibition of osteoclast activity. The objective of this study was to examine how occupancy of alpha(v)beta(3) integrins inhibits osteoclast function, using primary rat osteoclasts and murine pre-fusion osteoclast-like cells formed in a co-culture system. We show that: (1) echistatin inhibits bone resorption in vitro at lower concentrations (IC(50)= 0.1 nM) than those required to detach osteoclasts from bone (IC(50) approximately 1 microM); (2) echistatin (IC(50)= 0.1 nM) inhibits M-CSF-induced migration and cell spreading of osteoclasts; (3) alpha(v)beta(3) integrins are localized in podosomes at the leading edge of migrating osteoclasts, whereas, with echistatin treatment (0.1 nM), alpha(v)beta(3) disperses randomly throughout the adhesion surface; and (4) when bone resorption is fully inhibited with echistatin, there is visible disruption of the sealing zone (IC(50)= 13 nM), and alpha(v)beta(3) visualized with confocal microscopy re-distributes from the basolateral membranes to intracellular vesicular structures. Taken together, these findings suggest that alpha(v)beta(3) integrin plays a role in the regulation of two processes required for effective osteoclastic bone resorption: cell migration (IC(50)= 0.1 nM) and maintenance of the sealing zone (IC(50) approximately 10 nM).

scholarly journals Osteopontin Deficiency Produces Osteoclast Dysfunction Due to Reduced CD44 Surface Expression

2003 ◽  
Vol 14 (1) ◽  
pp. 173-189 ◽  
Author(s):  
M. A. Chellaiah ◽  
N. Kizer ◽  
R. Biswas ◽  
U. Alvarez ◽  
J. Strauss-Schoenberger ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Surface Expression ◽  
Wild Type ◽  
Exogenous Addition ◽  
Load To Failure ◽  
Ruffled Border ◽  
Osteoclast Function ◽  
Deficient Mice

Osteopontin (OPN) was expressed in murine wild-type osteoclasts, localized to the basolateral, clear zone, and ruffled border membranes, and deposited in the resorption pits during bone resorption. The lack of OPN secretion into the resorption bay of avian osteoclasts may be a component of their functional resorption deficiency in vitro. Osteoclasts deficient in OPN were hypomotile and exhibited decreased capacity for bone resorption in vitro. OPN stimulated CD44 expression on the osteoclast surface, and CD44 was shown to be required for osteoclast motility and bone resorption. Exogenous addition of OPN to OPN−/− osteoclasts increased the surface expression of CD44, and it rescued osteoclast motility due to activation of the αvβ3 integrin. Exogenous OPN only partially restored bone resorption because addition of OPN failed to produce OPN secretion into resorption bays as seen in wild-type osteoclasts. As expected with these in vitro findings of osteoclast dysfunction, a bone phenotype, heretofore unappreciated, was characterized in OPN-deficient mice. Delayed bone resorption in metaphyseal trabeculae and diminished eroded perimeters despite an increase in osteoclast number were observed in histomorphometric measurements of tibiae isolated from OPN-deficient mice. The histomorphometric findings correlated with an increase in bone rigidity and moment of inertia revealed by load-to-failure testing of femurs. These findings demonstrate the role of OPN in osteoclast function and the requirement for OPN as an osteoclast autocrine factor during bone remodeling.

scholarly journals Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2−/− mice

2007 ◽  
Vol 178 (6) ◽  
pp. 1053-1064 ◽  
Author(s):  
Hava Gil-Henn ◽  
Olivier Destaing ◽  
Natalie A. Sims ◽  
Kazuhiro Aoki ◽  
Neil Alles ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Protein Tyrosine Kinase ◽  
Ectopic Expression ◽  
Cell Periphery ◽  
Wild Type ◽  
Zone Formation ◽  
Sealing Zone ◽  
Osteoclast Function ◽  
Actin Rings

The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2−/− mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.

Hyperactivation of p21ras and PI3-K Cooperate To Alter Murine and Human NF1 Haploinsufficient Osteoclast Functions.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 675-675
Author(s):  
Shi Chen ◽  
Alexander Robling ◽  
Xiaohong Li ◽  
Jin Yuan ◽  
Janet Hock ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Genetic Disorder ◽  
Bone Matrix ◽  
Lytic Activity ◽  
Mineral Density ◽  
Local Bone ◽  
Osteoclast Function ◽  
K Activity

Abstract Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations of the NF1 tumor suppressor gene that functions as a GTPase activating protein for Ras. Though nullizygous loss of NF1 is associated with the development of malignancies, haploinsufficient phenotypes are now being increasingly recognized to alter cell fates and functions in a number of tissues resulting in nonmalignant disease manifestations. Bone manifestations, including skeletal dysplasias, scoliosis, and osteoporosis occur in 30–60% of all NF1 patients and osteoporosis is an increasingly recognized health problem for women with NF1. However, understanding of the cellular and molecular basis of these sequelae is incomplete. Osteoclasts are specialized myeloid cells that are the principal bone resorbing cells of the skeleton. Using an established murine model of NF1 developed using homologous recombination, we found that Nf1+/− mice contain elevated numbers of multinucleated osteoclasts and osteoclast progenitors per femur in vivo. Both osteoclasts and osteoclast progenitors from Nf1+/− mice were hyperresponsive to limiting concentrations of M-CSF and RANKL, growth factors that are integral to osteoclast maturation and activation. M-CSF stimulated p21ras-GTP and Akt phosphorylation was elevated in Nf1+/− osteoclasts associated with gains in function in survival and proliferation. Bone resorption by osteoclasts is linked to the migration and adherence of these cells to a local bone surface. Purified populations of Nf1+/− osteoclasts were initially placed in the upper chamber of a transwell coated with vitronectin and haptotaxis to M-CSF was determined. Nf1+/− osteoclasts had a 2–3 fold increase in migration as compared to syngeneic wildtype cells. A similar increase in adhesion of Nf1+/− osteoclasts to the integrin avb3 was also observed. Following adhesion, osteoclasts form a specialized cell-extracellular matrix to initiate degradation of bone matrix by secreting proteinases. Nf1+/− osteoclasts had significantly increased bone resorption as measured by scoring the number and area of individual bone resorbing “pits” on dentine slices and by scoring the total area of resorption. These collective increases in osteoclast function were validated in vivo by the observation that serum TRAP5b activity, a sensitive measure of osteoclast lytic activity was 2.5 fold higher in Nf1+/− mice as compared to WT mice. Furthermore, we performed ovariectomy, an established model of osteoporosis associated with an increase in osteoclast function. In two independent experiments, we found that Nf1+/− mice had a significantly greater reduction in bone mineral density following ovariectomy as compared to syngeneic wildtype mice. We hypothesized that hyperactivation of class1A-PI3-K may contribute to these gains in cellular function. We found that intercrossing Nf1+/− and Class1A PI3-K deficient mice (p85a) restores elevated PI3-K activity, and Nf1+/− osteoclast functions to wildtype levels. Furthermore, in vitro differentiated osteoclasts from NF1 patients also display elevated Ras-PI3-K activity and increased lytic activity analogous to murine Nf1+/− osteoclasts. Collectively, we identify a novel cellular and biochemical NF1 haploinsufficient phenotype in osteoclasts that has potential implications in the pathogenesis of NF1 bone disease.

Rac1, but Not Rac2, Mediates Osteoclast Gain-of-Function Induced by Nf1 Haploinsufficiency.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 237-237
Author(s):  
Shi Chen ◽  
Jincheng Yan ◽  
Yingze Zhang ◽  
Yan Li ◽  
Xiaohong Li ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Critical Role ◽  
Bone Diseases ◽  
Type I ◽  
Filamentous Actin ◽  
Mineral Density ◽  
Gain Of Function ◽  
Hematopoietic Stem ◽  
Sealing Zone ◽  
Osteoclast Function

Abstract Neurofibromatosis type I (NF1) is a congenital disorder resulting from loss-of-function of the tumor suppressor gene, NF1. 50% of NF1 patients have osseous manifestations, including short stature, scoliosis, and reduced bone mineral density. Osteoclasts are hematopoietic stem cell-derived cells that function to resorb bone. We recently reported that osteoclasts derived from NF1 patients and Nf1 heterozygous (Nf1+/−) mice have elevated migration, adhesion, and bone resorption and our studies indicate that the gain-of-function of the Nf1+/− osteoclasts is, at least in part, caused by hyperactivation of macrophage colony-stimulating factor (M-CSF)-stimulated Ras, phosphoinositol-3-kinase (PI3K), and Erk. Rho GTPases function downstream of Ras and PI3K and act as binary switches, cycling between an inactive (GDP-bound) and active (GTP-bound) state, to regulate osteoclast actin ring formation, bone resorption, and development of filamentous actin structures associated with migration and adhesion. We hypothesized that hyperactivation of Rac1, Rac2, or both Rac1 and Rac2 contribute to the increased osteoclast function observed in Nf1+/− mice and NF1 patients. To examine this hypothesis, we intercrossed Nf1+/− mice with conditional Rac1flox/floxMxcre+ mice or with Rac2−/− mice to generate WT, Nf1+/−, Rac1−/−, Nf1+/−;Rac1−/−, Rac2−/−, and Nf1+/−;Rac2−/− mice. Genetic disruption of Rac1, but not of Rac2, restored the increased colony forming unit-macrophage (CFU-M), tatrate resistant acid phosphate+ (TRAP+) CFU-M, osteoclast migration, and bone resorption observed in Nf1+/− cultures. Osteoclast bone resorbing capacity is dependent on the organization of the actin cytoskeleton into a large f-actin-rich structure referred to as the sealing zone. The podosome belt evolves into the sealing zone in actively resorbing osteoclasts. A significantly higher level of belt formation, seen in mature osteoclasts, was observed in Nf1+/− cultures as compared to WT. Upon genetic deletion of Rac1, the Nf1+/−;Rac1−/− osteoclasts demonstrated belt formation at a similar level to that of WT osteoclasts. These data indicate that Rac1 plays an essential role in functional f-actin organization and suggest that inhibition of Rac1 in the setting of Nf1 haploinsufficiency is able to normalize osteoclast hyperactivity by correcting the cytoskeletal organization of f-actin-based structures. Mechanistically, Rac1 deficiency normalized M-CSF-stimulated phospho-Erk and phospho-Akt and pharmacologic inhibition of MEK and PI3K using PD98059 or Ly294002, respectively, normalized Nf1+/− osteoclast development and maturation. The critical role of Rac1, but not of Rac2, in osteoclast function is significant as it suggests that the Rac GTPases contribute non-redundant functions in various myeloid cell types and imply that blocking Rac1 function, while sparing that of Rac2, may provide a level of specificity to therapeutics for skeletal diseases. Collectively, these data demonstrate that Rac1 critically contributes to increased osteoclast function induced by haploinsufficiency of Nf1 and imply that Rac1 may be a rational therapeutic target for dysplastic and erosive bone diseases.

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