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Melda Onal,
Marilina Piemontese,
Jinhu Xiong,
Yiying Wang,
Li Han,
Shiqiao Ye,
Masaaki Komatsu,
Martin Selig,
Robert S Weinstein, Haibo Zhao,
Robert L Jilka,
Maria Almeida,
Stavros C Manolagas,
Charles A O'Brien
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ABSTRACT: Bone mass declines with age but the mechanisms responsible remain unclear. Here we demonstrate that deletion of a conditional allele for Atg7, a gene essential for autophagy, from osteocytes caused low bone mass in 6-month-old male and female mice. Cancellous bone volume and cortical thickness were decreased, and cortical porosity increased, in conditional knockout mice compared with control littermates. These changes were associated with low osteoclast number, osteoblast number, bone formation rate, and wall width in the cancellous bone of conditional knockout mice. In addition, oxidative stress was higher in the bones of conditional knockout mice as measured by reactive oxygen species levels in the bone marrow and by p66shc phosphorylation in L6 vertebra. Each of these changes has been previously demonstrated in the bones of old versus young adult mice. Thus, these results demonstrate that suppression of autophagy in osteocytes mimics, in many aspects, the impact of aging on the skeleton and suggest that a decline in autophagy with age may contribute to the low bone mass associated with aging.
Journal of Biological Chemistry 05/2013; · 4.77 Impact Factor
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ABSTRACT: Osteoclastic bone resorption requires strict interplay between acidified carrier vesicles, motor proteins and the underlying cytoskeleton in order to sustain the specialized structural and functional polarization of the ruffled border. Cytoplasmic dynein, a large processive mechanochemical motor comprising heavy, intermediate and light chains coupled to the dynactin co-factor complex, powers unilateral motility of diverse cargos to microtubule minus-ends. We have recently shown that regulators of the dynein motor complex constitute critical components of the osteoclastic bone resorptive machinery. Here, by selectively modulating endogenous dynein activity we demonstrate that the integrity of the dynein-dynactin motor complex is an essential requirement for both osteoclast formation and function. Systematic dissection of the osteoclast dynein-dynactin complex revealed that it is differentially localized throughout RANKL-induced osteoclast formation and activation, undergoing microtubule-coupled reorganization upon the establishment of cellular polarization. In osteoclasts actively resorbing bone, dynein-dynactin intimately co-localizes with the CAP-Gly domain-containing microtubule plus-end protein CLIP-170 at the resorptive front, thus orientating the ruffled border as a microtubule plus-end domain. Unexpectedly, disruption of the dynein-dynactin complex by exogenous p50/dynamitin expression retards osteoclast formation in vitro, owing largely to prolonged mitotic stasis of osteoclast progenitor cells. More importantly, loss of osteoclastic dynein activity results in a drastic redistribution of key intracellular organelles including the Golgi and lysosomes, an effect that coincides with impaired cathepsin K secretion and diminished bone resorptive function. Collectively, these data unveil a previously unrecognized role for the dynein-dynactin motor complex in osteoclast formation and function, serving not only to regulate their timely maturation but also the delivery of osteolytic cargo that is essential to the bone resorptive process. © 2012 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2012; · 6.04 Impact Factor
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Haibo Zhao
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ABSTRACT: The endocytic and exocytic/secretory pathways are two major intracellular membrane trafficking routes that regulate numerous cellular functions in a variety of cell types. Osteoblasts and osteoclasts, two major bone cells responsible for bone remodeling and homeostasis, are no exceptions. During the past few years, emerging evidence has pinpointed a critical role for endocytic and secretory pathways in osteoblast and osteoclast differentiation and function. The endosomal membrane provides a platform to integrate bone tropic signals of hormones and growth factors in osteoblasts. In osteoclasts, endocytosis, followed by transcytosis, of degraded bone matrix promotes bone resorption. Secretory pathways, especially lysosome secretion, not only participate in bone matrix deposition by osteoblasts and degradation of mineralized bone matrix by osteoclasts; they may also be involved in the coupling of bone resorption and bone formation during bone remodeling. More importantly, mutations in genes encoding regulatory factors within the endocytic and secretory pathways have been identified as causes for bone diseases. Identification of the molecular mechanisms of these genes in bone cells may provide new therapeutic targets for skeletal disorders.
Traffic 07/2012; 13(10):1307-14. · 4.92 Impact Factor
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ABSTRACT: The adverse skeletal effects of glucocorticoid excess are due to increased osteoclast survival, decreased production of osteoblasts, and increased apoptosis of osteoblasts and osteocytes, but it remains unknown which of these is the principle cause of the decrease in bone strength. Previous studies suggested that osteocytes contribute to bone strength independently of changes in bone mass. Administration of the receptor activator for nuclear factor κB ligand (RANKL) antagonist osteoprotegerin (OPG) rapidly decreases osteoclasts followed by a decrease in osteoblasts but should not affect the long-lived osteocytes. Therefore, to distinguish between glucocorticoid effects on osteoclasts, osteoblasts, or osteocytes, we administered glucocorticoids, alone or in combination with OPG with the fragment crystallizable region of Ig heavy chains (OPG-Fc), to mice. The suppressive effect of glucocorticoids on spinal bone mineral density, cortical thickness, and strength was prevented by OPG-Fc. OPG-Fc, with or without glucocorticoids, profoundly reduced osteoclasts, osteoblasts, and bone formation. Unexpectedly, OPG-Fc prevented the glucocorticoid-induced increase in osteocyte apoptosis and reduction in solute transport from the systemic circulation to the osteocyte-lacunar-canalicular network. The fluid in the osteocyte-lacunar-canalicular network was inversely related to osteocyte apoptosis and directly related to bone mineral density. Consistent with the in vivo findings, Both OPG-Fc and OPG decreased glucocorticoid-induced apoptosis of MLO-Y4 osteocytic cells. OPG can also bind and antagonizes the activity of the TNF-related apoptosis-inducing ligand (TRAIL), but glucocorticoids did not change TRAIL expression, and knockdown of TRAIL did not prevent OPG-Fc from reducing glucocorticoid-induced osteocyte apoptosis. Based on these results, we conclude that at least part of the OPG-induced preservation of bone strength is due to the maintenance of osteocyte viability and the lacunar-canalicular network.
Endocrinology 09/2011; 152(9):3323-31. · 4.46 Impact Factor
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ABSTRACT: Osteoclasts are specialized cells that secrete lysosomal acid hydrolases at the site of bone resorption, a process critical for skeletal formation and remodeling. However, the cellular mechanism underlying this secretion and the organization of the endo-lysosomal system of osteoclasts have remained unclear. We report that osteoclasts differentiated in vitro from murine bone marrow macrophages contain two types of lysosomes. The major species is a secretory lysosome containing cathepsin K and tartrate-resistant acid phosphatase (TRAP), two hydrolases critical for bone resorption. These secretory lysosomes are shown to fuse with the plasma membrane, allowing the regulated release of acid hydrolases at the site of bone resorption. The other type of lysosome contains cathepsin D, but little cathepsin K or TRAP. Osteoclasts from Gnptab(-/-) (gene encoding GlcNAc-1-phosphotransferase α, β-subunits) mice, which lack a functional mannose 6-phosphate (Man-6-P) targeting pathway, show increased secretion of cathepsin K and TRAP and impaired secretory lysosome formation. However, cathepsin D targeting was intact, showing that osteoclasts have a Man-6-P-independent pathway for selected acid hydrolases.
Traffic 04/2011; 12(7):912-24. · 4.92 Impact Factor
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ABSTRACT: Microtubule organization and lysosomal secretion are both critical for the activation and function of osteoclasts, highly specialized polykaryons that are responsible for bone resorption and skeletal homeostasis. Here, we have identified a novel interaction between microtubule regulator LIS1 and Plekhm1, a lysosome-associated protein implicated in osteoclast secretion. Decreasing LIS1 expression by shRNA dramatically attenuated osteoclast formation and function, as shown by a decreased number of mature osteoclasts differentiated from bone marrow macrophages, diminished resorption pits formation, and reduced level of CTx-I, a bone resorption marker. The ablated osteoclast formation in LIS1-depleted macrophages was associated with a significant decrease in macrophage proliferation, osteoclast survival and differentiation, which were caused by reduced activation of ERK and AKT by M-CSF, prolonged RANKL-induced JNK activation and declined expression of NFAT-c1, a master transcription factor of osteoclast differentiation. Consistent with its critical role in microtubule organization and dynein function in other cell types, we found that LIS1 binds to and colocalizes with dynein in osteoclasts. Loss of LIS1 led to disorganized microtubules and aberrant dynein function. More importantly, the depletion of LIS1 in osteoclasts inhibited the secretion of Cathepsin K, a crucial lysosomal hydrolase for bone degradation, and reduced the motility of osteoclast precursors. These results indicate that LIS1 is a previously unrecognized regulator of osteoclast formation, microtubule organization, and lysosomal secretion by virtue of its ability to modulate dynein function and Plekhm1.
PLoS ONE 01/2011; 6(11):e27285. · 4.09 Impact Factor
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ABSTRACT: The modeling and remodeling of bone requires activation and polarization of osteoclasts, achieved by reorganization of the cytoskeleton. Members of the Rho subfamily of small GTPases, including Cdc42, are known regulators of cytoskeletal components, but the role of these proteins in bone physiology and pathophysiology remains unclear. Here, we examined loss-of-function mice in which Cdc42 was selectively ablated in differentiated osteoclasts and gain-of-function animals wherein Cdc42Gap, a protein that inactivates the small GTPase, was deleted globally. Cdc42 loss-of-function mice were osteopetrotic and resistant to ovariectomy-induced bone loss, while gain-of-function animals were osteoporotic. Isolated Cdc42-deficient osteoclasts displayed suppressed bone resorption, while osteoclasts with increased Cdc42 activity had enhanced resorptive capacity. We further demonstrated that Cdc42 modulated M-CSF-stimulated cyclin D expression and phosphorylation of Rb and induced caspase 3 and Bim, thus contributing to osteoclast proliferation and apoptosis rates. Furthermore, Cdc42 was required for multiple M-CSF- and RANKL-induced osteoclastogenic signals including activation and expression of the differentiation factors MITF and NFATc1 and was a component of the Par3/Par6/atypical PKC polarization complex in osteoclasts. These data suggest that Cdc42 regulates osteoclast formation and function and may represent a promising therapeutic target for prevention of pathological bone loss.
The Journal of clinical investigation 06/2010; 120(6):1981-93. · 15.39 Impact Factor
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ABSTRACT: Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)alpha from the monocyte/macrophage cell lineage in mice (ERalpha(LysM)(-/-)) and found a 2-fold increase in osteoclast progenitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERalpha(LysM)(-/-) were resistant to the proapoptotic effect of 17beta-estradiol. Nonetheless, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERalpha knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERalpha was as effective as 17beta-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERalpha. We conclude that estrogens attenuate osteoclast generation and life span via cell autonomous effects mediated by DNA-binding-independent actions of ERalpha. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subsequent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton.
Molecular Endocrinology 02/2010; 24(2):323-34. · 4.54 Impact Factor
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ABSTRACT: The ruffled border is the most specific marker of the active osteoclast (OC) as it forms only when the cell is resorbing bone. We provide evidence that this complex cytoskeletal structure reflects insertion of the lysosomal vesicles into the bone-apposed plasma membrane under the aegis of the Ca-sensing, exocytic protein, synaptotagmin VII (SytVII). In the manner, SytVII permits transport of matrix-degrading molecules into the resorptive microenvironment. SytVII also regulates secretion of bone matrix molecules by osteoblasts. Thus, SytVII-deficient mice experience suppressed bone resorption and formation with the latter deficiency predominant thereby yielding osteoporosis characterized by attenuated remodeling.
Advances in experimental medicine and biology 01/2010; 658:105-9. · 1.09 Impact Factor
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ABSTRACT: Recent studies support the notion that there is an intricate relationship between hematopoiesis and bone homeostasis in normal steady states. Using mice undergoing chronic inflammatory arthritis, we investigated the relationship between hematopoiesis and bone homeostasis in pathologic conditions. We demonstrate that mice undergoing chronic inflammatory arthritis displayed osteoporosis resulting from a severe defect in osteoblast function. Despite the defective osteoblast function, however, the hematopoietic stem cells from these mice exhibited normal properties in either long-term repopulation or cell cycling. Therefore, the bone-forming capacity of osteoblasts is distinct from their ability to maintain hematopoietic stem cells in chronic inflammatory conditions.
Blood 09/2009; 114(20):4402-10. · 9.90 Impact Factor
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ABSTRACT: Cytoskeletal organization of the osteoclast (OC), which is central to the capacity of the cell to resorb bone, is induced by occupancy of the alphavbeta3 integrin or the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. In both circumstances, the tyrosine kinase Syk is an essential signaling intermediary. We demonstrate that Cbl negatively regulates OC function by interacting with Syk(Y317). Expression of nonphosphorylatable Syk(Y317F) in primary Syk(-/-) OCs enhances M-CSF- and alphavbeta3-induced phosphorylation of the cytoskeleton-organizing molecules, SLP76, Vav3, and PLCgamma2, to levels greater than wild type, thereby accelerating the resorptive capacity of the cell. Syk(Y317) suppresses cytoskeletal organization and function while binding the ubiquitin-protein isopeptide ligase Cbl. Consequently, Syk(Y317F) abolishes M-CSF- and integrin-stimulated Syk ubiquitination. Thus, Cbl/Syk(Y317) association negatively regulates OC function and therefore is essential for maintenance of skeletal homeostasis.
Journal of Biological Chemistry 06/2009; 284(28):18833-9. · 4.77 Impact Factor
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ABSTRACT: Melanoma is the most serious, highly aggressive form of skin cancer with recent dramatic increases in incidence. Current therapies are relatively ineffective, highlighting the need for a better understanding of the molecular mechanisms contributing to the disease. We have previously shown that activation of Rap1 promotes melanoma cell proliferation and migration through the mitogen-activated protein kinase pathway and integrin activation. In the present study, we show that expression of Rap1GAP, a specific negative regulator of Rap1, is decreased in human melanoma tumors and cell lines. Overexpression of Rap1GAP in melanoma cells blocks Rap1 activation and extracellular signal-regulated kinase (ERK) phosphorylation and inhibits melanoma cell proliferation and survival. In addition, overexpression of Rap1GAP also inhibits focal adhesion formation and decreases melanoma cell migration. Rap1GAP down-regulation is due to its promoter methylation, a mechanism of gene silencing in tumors. Furthermore, treatment of melanoma cells with the demethylating agent 5-aza-2'-deoxycytidine reinduces Rap1GAP expression, followed by decreased Rap1 activity, ERK phosphorylation, and cell proliferation and survival-changes that are significantly blunted in cells transfected by small interfering RNA-mediated Rap1GAP knockdown. Taken together, our findings indicate that down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.
Cancer Research 02/2009; 69(2):449-57. · 7.86 Impact Factor
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ABSTRACT: Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with the cytoplasmic domain of receptor activator of NF-kappaB (RANK) and is an essential component of the signaling complex mediating osteoclastogenesis. However, the osteoclastic activity of TRAF6 is blunted by its association with four and half LIM domain 2 (FHL2), which functions as an adaptor protein in the cytoplasm and transcriptional regulator in the nucleus. We find that TRAF6 also localizes in the nuclei of osteoclasts but not their bone marrow macrophage precursors and that osteoclast intranuclear abundance is specifically increased by RANK ligand (RANKL). TRAF6 nuclear localization requires FHL2 and is diminished in fhl2(-/-) osteoclasts. Suggesting transcriptional activity, TRAF6 interacts with the transcription factor RUNX1 in the osteoclast nucleus. FHL2 also associates with RUNX1 but does so only in the presence of TRAF6. Importantly, TRAF6 recognizes FHL2 and RUNX1 in osteoclast nuclei, and the three molecules form a DNA-binding complex that recognizes and transactivates the RUNX1 response element in the fhl2 promoter. Finally, TRAF6 and its proximal activator, RANKL, polyubiquitinate FHL2, prompting its proteasomal degradation. These observations suggest a feedback mechanism whereby TRAF6 negatively regulates osteoclast formation by intracytoplasmic sequestration of FHL2 to blunt RANK activation and as a component of a transcription complex promoting FHL2 expression.
Journal of Biological Chemistry 10/2008; 283(45):30861-7. · 4.77 Impact Factor
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ABSTRACT: Maintenance of bone mass and integrity requires a tight balance between resorption by osteoclasts and formation by osteoblasts. Exocytosis of functional proteins is a prerequisite for the activity of both cells. In the present study, we show that synaptotagmin VII, a calcium sensor protein that regulates exocytosis, is associated with lysosomes in osteoclasts and bone matrix protein-containing vesicles in osteoblasts. Absence of synaptotagmin VII inhibits cathepsin K secretion and formation of the ruffled border in osteoclasts and bone matrix protein deposition in osteoblasts, without affecting the differentiation of either cell. Reflecting these in vitro findings, synaptotagmin VII-deficient mice are osteopenic due to impaired bone resorption and formation. Therefore, synaptotagmin VII plays an important role in bone remodeling and homeostasis by modulating secretory pathways functionally important in osteoclasts and osteoblasts.
Developmental cell 07/2008; 14(6):914-25. · 13.36 Impact Factor
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Matthew J Hilton,
Xiaolin Tu,
Ximei Wu,
Shuting Bai, Haibo Zhao,
Tatsuya Kobayashi,
Henry M Kronenberg,
Steven L Teitelbaum,
F Patrick Ross,
Raphael Kopan,
Fanxin Long
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ABSTRACT: Postnatal bone marrow houses mesenchymal progenitor cells that are osteoblast precursors. These cells have established therapeutic potential, but they are difficult to maintain and expand in vitro, presumably because little is known about the mechanisms controlling their fate decisions. To investigate the potential role of Notch signaling in osteoblastogenesis, we used conditional alleles to genetically remove components of the Notch signaling system during skeletal development. We found that disruption of Notch signaling in the limb skeletogenic mesenchyme markedly increased trabecular bone mass in adolescent mice. Notably, mesenchymal progenitors were undetectable in the bone marrow of mice with high bone mass. As a result, these mice developed severe osteopenia as they aged. Moreover, Notch signaling seemed to inhibit osteoblast differentiation through Hes or Hey proteins, which diminished Runx2 transcriptional activity via physical interaction. These results support a model wherein Notch signaling in bone marrow normally acts to maintain a pool of mesenchymal progenitors by suppressing osteoblast differentiation. Thus, mesenchymal progenitors may be expanded in vitro by activating the Notch pathway, whereas bone formation in vivo may be enhanced by transiently suppressing this pathway.
Nature medicine 04/2008; 14(3):306-14. · 27.14 Impact Factor
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ABSTRACT: A tight balance between bone resorption by osteoclasts and bone formation by osteoblasts is required for the maintenance of bone mass and integrity. A net increase in bone resorption over formation results in osteoporosis, a disease associated with significantly morbidity and mortality. Following attachment via the integrin alphavbeta3, osteoclasts degrade bone by generation of the ruffled border, the unique resorptive organelle of the cell. The adherent cell then secretes into the subcellular space protons and acidic proteases. We review here the concepts relating to the mechanisms of regulated secretion and provide preliminary data on the role of one protein important for secretion by osteoclasts.
Annals of the New York Academy of Sciences 12/2007; 1116:238-44. · 3.15 Impact Factor
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ABSTRACT: Glucocorticoid (GC)-induced bone loss is the most common cause of secondary osteoporosis but its pathogenesis is controversial. GCs clearly suppress bone formation in vivo but the means by which they impact osteoblasts is unclear. Because bone remodeling is characterized by tethering of the activities of the two cells, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To address this issue we compared the effects of dexamethasone on wild-type (WT) osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells and found that the bone-degrading capacity of GC-treated WT cells is suppressed. The inhibitory effect of dexamethasone on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. Dexamethasone specifically arrests M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances, mice lacking the GC receptor in osteoclast lineage cells are spared the impact of dexamethasone on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of dexamethasone, GC receptor-deficient mice are protected from the steroid's inhibition of bone formation.
Annals of the New York Academy of Sciences 12/2007; 1116:335-9. · 3.15 Impact Factor
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ABSTRACT: Cardiac hypertrophy commonly develops in response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the activation of transmembrane integrin alphabeta heterodimers that are expressed in cardiomyocytes. Once activated, integrins stimulate focal adhesion kinase, Grb2, c-src, and other signaling molecules to promote cardiomyocyte growth and gene expression. Mechanical stress can also promote cardiac inflammation that may be mediated, in part, by the activation of integrins expressed in blood-borne cells. To address the role of one integrin, beta(3), in the pathogenesis of cardiac hypertrophy, beta(3)(-/-) mice were examined. beta(3)(-/-) Mice developed moderate spontaneous cardiac hypertrophy associated with systolic and diastolic dysfunction, and these abnormalities were exacerbated by transverse aortic constriction. In addition, beta(3)(-/-) mice developed mild cardiac inflammation with infiltrating macrophages at baseline that was markedly worsened by pressure overload. Bone marrow transplantation experiments showed that blood-borne cells were at least partially responsible for the cardiac hypertrophy and inflammation observed in beta(3)(-/-) mice. These results suggest that alpha(v)beta(3) expression in bone marrow has a generalized suppressive effect on cardiac inflammation.
Journal of Molecular and Cellular Cardiology 03/2007; 42(2):367-77. · 5.17 Impact Factor
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ABSTRACT: Increasingly a number of proteins important in the regulation of bone osteoclast development have been shown primarily influence osteoclastogenesis under conditions of physiologic or pathologic stress. Why basal osteoclastogenesis is normal and how these proteins regulate stress osteoclastogenic responses, as opposed to basal osteoclastogenesis, is unclear. LIM proteins of the Ajuba/Zyxin family localize to cellular sites of cell adhesion where they contribute to the regulation of cell adhesion and migration, translocate into the nucleus where they can affect cell fate, but are also found in the cytoplasm where their function is largely unknown. We show that one member of this LIM protein family, Limd1, is uniquely up-regulated during osteoclast differentiation and interacts with Traf6, a critical cytosolic regulator of RANK-L-regulated osteoclast development. Limd1 positively affects the capacity of Traf6 to activate AP-1, and Limd1(-/-) osteoclast precursor cells are defective in the activation of AP-1 and thus induction of NFAT2. Limd1(-/-) mice, although having normal basal bone osteoclast numbers and bone density, are resistant to physiological and pathologic osteoclastogenic stimuli. These results implicate Limd1 as a potentially important regulator of osteoclast development under conditions of stress.
Journal of Biological Chemistry 02/2007; 282(1):39-48. · 4.77 Impact Factor
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ABSTRACT: Glucocorticoids are central to treating inflammatory and immune disorders. These steroids, however, profoundly impact the skeleton, particularly when administered for prolonged periods. In fact, high-dose glucocorticoid therapy is almost universally associated with bone loss, prompting among the most common forms of crippling osteoporosis. Despite the frequency and severity of glucocorticoid-induced osteoporosis, its treatment is less than satisfactory, suggesting that its pathogenesis is incompletely understood. Net bone mass represents the relative activities of osteoblasts and osteoclasts and there is little question that glucocorticoids suppress the bone-forming cells, in vivo, via a process involving accelerated apoptosis (Weinstein 2001; Weinstein, Jilka, Parfitt, et al. 1998). Surprisingly, however, addition of glucocorticoids to cultures of osteoprogenitor cells actually increases their capacity to form mineralized bone nodules (Aubin 1999; Purpura, Aubin, and Zandstra 2004). This paradox raises the possibility that glucocorticoid suppression of bone formation, in vivo, reflects, at least in part, the steroid's targeting intermediary cells, which in turn inhibit the osteoblast. Bone remodeling is an ever-occuring event in mammals which is characterized by tethering of osteoclast and osteoblast function. The process is initiated by osteoclasts (OCs) resorbing a packet of bone, which in turn leads to osteoblasts being recruited to the site of resorption. This process establishes that osteoclastic bone resorption, in some manner, promotes osteoblastic bone formation at the same location. Consequently, pathologically or pharmacologically inhibited resorption eventuates in arrested osteoblast activity.
Advances in experimental medicine and biology 02/2007; 602:43-6. · 1.09 Impact Factor
