Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo.

Yoneda, Toshiyuki; Lowe, Carolyn; Lee, Chang-Ho; Gutiérrez, Gloria; Niewolna, Maria; Williams, Paul J.; Izbicka, Elzbieta; Uehara, Yoshimasa; Mundy, Gregory R.

doi:10.1172/jci116521

Cited by 87 publications

(58 citation statements)

References 17 publications

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“…Resorption pit formation by TRAP( + )MNC or isolated mature mouse osteoclasts on calcified matrix was determined according to the technique previously described (10,14), which was originally developed by Boyde et al (15). Sperm whale dentine (0.25 x 7 x 7 mm) was prepared using a Buehler low speed diamond saw (Buehler, Lake Bluff, IL) followed by sonication (15 min) resorption pits were stained with 0.1% (wt/vol) toluidine blue (Sigma) solution.…”

Section: Methodsmentioning

confidence: 99%

The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow.

Mbalaviele¹,

Chen²,

Boyce³

et al. 1995

J. Clin. Invest.

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154

112

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Section: Methodsmentioning

confidence: 99%

The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow.

Mbalaviele¹,

Chen²,

Boyce³

et al. 1995

J. Clin. Invest.

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154

112

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“…Antisense Suppression of Src during Osteoclast Differentiation-It has previously been shown that antisense suppression of Src or use of a tyrosine kinase inhibitor decreases the ability of osteoclasts to resorb bone (27,28,51). Whether disruption of c-Src affects acid transport by osteoclasts has not previously been investigated.…”

Section: C-src Control Of Osteoclast Hcl Transportmentioning

confidence: 99%

“…Microscopically, osteoclasts from these mice were described to be elongated and have rudimentary or absent ruffled borders (26). Therefore it appears that c-Src and its downstream signaling pathways support bone resorption by mature osteoclasts by allowing full development of the ruffled border (27)(28)(29). A direct role for Src in support of osteoclast acid transport has not been determined, but it is clearly required to develop a functional ruffled border (2,30).…”

mentioning

confidence: 99%

c-Src Control of Chloride Channel Support for Osteoclast HCl Transport and Bone Resorption

Edwards

Cohen

et al. 2006

Journal of Biological Chemistry

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Bone degradation by osteoclasts depends upon active transport of hydrogen ions to solubilize bone mineral. This transport is supported by the parallel actions of a proton ATPase and a chloride channel located in the osteoclast ruffled membrane. We have previously identified a novel chloride channel, p62, which appears to be the avian counterpart to CLIC-5b and is expressed coincident with the appearance of acid secretion as avian osteoclasts differentiate in culture. In this article, we show that suppression of CLIC-5b in differentiating avian osteoclasts results in decreased acidification by vesicles derived from these cells and decreased ability of the cells to resorb bone. Acidification is rescued by the presence of valinomycin, consistent with a selective loss of chloride channel but not proton pump activity. Osteoclast bone resorption is known to be dependent on the expression of the tyrosine kinase, c-Src. We show that CLIC-5b from osteoclasts has affinity for both Src SH2 and SH3 domains. We find that suppression of expression of Src in developing osteoclasts results in decreased vesicular acidification, which is rescued by valinomycin, consistent with the loss of chloride conductance in the proton pump-containing vesicles. Suppression of c-Src causes no change in the steady state level of CLIC-5b expression, but does result in failure of proton pump and CLIC-5b to colocalize in cultured osteoclast precursors. We conclude that suppression of c-Src interferes with osteoclast bone resorption by disrupting functional co-localization of proton pump and CLIC-5b.Skeleton integrity requires that osteoclast-mediated bone resorption be intact and regulated (1). Osteoclasts can remodel bone because these multinucleated cells secret sufficient acid into the resorption compartment to solubilize bone mineral (2, 3), an alkaline salt that becomes increasingly soluble at pH values below 6 (4, 5). The resorption compartment is delineated by a circumferential tightly adherent sealing zone (6). The osteoclast plasma membrane enclosed within the sealing zone differentiates into a highly specialized structure, the ruffled border. Across this membrane the cell actively transports HCl, which dissolves bone mineral and activates acid hydrolases required for bone resorption (7,8). The transport of HCl occurs in two steps. An electrogenic ATP-dependent proton pump (9 -12), inserts H ϩ into the resorption compartment. Chloride ions follow passively through a parallel chloride conductance, short circuiting the electrogenic pump and allowing the massive HCl secretion necessary during bone resorption (10).We had previously identified a 62-kDa protein, p62, from avian osteoclast ruffled border that could be reconstituted to form a DNDS 2 -sensitive chloride channel (13). This protein is antigenically related to bovine CLIC-5b, a chloride channel of bovine kidney microsomal membranes (14). Expression of avian p62 in differentiating avian osteoclasts is coincident with the appearance of outwardly rectifying chloride conductance, valinom...

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“…These data suggest that both receptor and nonreceptor tyrosine kinases may be required for normal osteoclast formation and action. The drug herbimycin A, which is an effective inhibitor of the src tyrosine kinase (among other tyrosine kinases), effectively lowers the serum calcium and decreases osteoclastic bone resorption in vivo [49].…”

Section: Role Of Tyrosine Kinases In Osteociastic Bone Resorptionmentioning

confidence: 99%

Role of cytokines in bone resorption

Mundy

1993

J of Cellular Biochemistry

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Osteoclastic bone resorption is modulated in humans by powerful osteotropic factors which are generated in the immediate vicinity of bone resorbing surfaces. These factors are released from marrow mononuclear cells and from some bone cells, and some are actually incorporated into the noncollagenous bone matrix from where they are released when bone i s resorbed. They are likely important not only in the control of normal bone remodeling, but also in a number of disease states associated with disordered remodeling. In this review, current concepts of the effects of these factors on cells in the osteoclast lineage will be discussed. v 1993 WiIey-Liss, Inc. Key words: osteoclasts, bone resorption, cytokines, srcIn the last 20 years, it has become apparent that the process of bone resorption is regulated not only by systemic hormones such as parathyroid hormone and 1,25 dihydroxyvitamin D, but in addition by a large number of powerful osteotropic factors which are generated locally in the bone cell microenvironment. These factors probably have more important effects on osteoclast function than do the systemic hormones, whose major role is the control of extracellular fluid calcium homeostasis. Bone resorption is the process by which small packets of bone throughout the skeleton are removed by osteoclastic resorption to be later replaced by osteoblastic bone formation. Since the resorption of bone occurs in discrete packets which are geographically and chronologically separate one from another, it has always appeared likely that the primary control of this process is mediated by local factors generated in the microenvironment of each bone remodeling packet.The first observation that cytokines may stimulate osteoclastic bone resorption was made over 20 years ago, when it was demonstrated that peripheral blood leukocytes activated by antigens to which they had previously been exposed or by phytohemagglutinin released a factor into their cell culture media which stimu- lated osteoclasts to resorb bone in organ cultures of fetal rat long bones [1,21. This lymphokine, as it was thought to be at the time, was termed osteoclast activating factor, or OAF. Since that time, it has become recognized that OAF is comprised of a number of discrete peptides, some of which stimulate osteoclastic bone resorption and some of which inhibit osteoclastic bone resorption. It has also become apparent that the factors which comprise this activity may be important in the bone loss which occurs in a number of pathologic states, and particularly chronic inflammatory diseases which cause bone loss, certain neoplasms associated with bone resorption, in osteopetrosis where failure of production of cytokines is likely important, and, most importantly, in the bone loss associated with the postmenopausal state and aging, namely osteoporosis.The cytokines which are involved in osteoclastic bone resorption are produced by marrow mononuclear cells and by bone cells, and some may be even incorporated into the nonmineralized bone matrix and relea...

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Herbimycin A, a pp60c-src tyrosine kinase inhibitor, inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo.

Cited by 87 publications

References 17 publications

The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow.

The role of cadherin in the generation of multinucleated osteoclasts from mononuclear precursors in murine marrow.

c-Src Control of Chloride Channel Support for Osteoclast HCl Transport and Bone Resorption

Role of cytokines in bone resorption

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