Biology of the Osteoclast

Baron, Roland; Chakraborty, Munmun; Chatterjee, Diptendu; Horne, William C.; Lomri, Abderrahim; Ravesloot, Jan H.

doi:10.1007/978-3-642-77991-6_3

Cited by 26 publications

(18 citation statements)

References 130 publications

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“…The association of pp60 ~ .... with secretory granules and vesicles has also been reported in platelets (37), chromaflin cells (22,36), neurons (1,24), and PC12 cells (31), further suggesting that the protein may contribute to vesicle targeting or membrane fusion. In the osteoclast, targeted delivery of intracellular vesicles to the apical surface of the cell is required to secrete enzymes into the resorption compartment and to insert the proton pump and other transporters involved in acid secretion at the apical ruffled border membrane (2). Although the apparent association of pp60 ~-src with intracellular vesicles in the osteoclast is consistent with this possible function, further work will be required to clarify this issue.…”

Section: Discussionmentioning

confidence: 99%

Osteoclasts express high levels of pp60c-src in association with intracellular membranes.

Horne

Neff

Chatterjee

et al. 1992

The Journal of Cell Biology

213

135

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Deletion of the c-src gene in transgenic mice by homologous recombination leads to osteopetrosis, a skeletal defect characterized by markedly deficient bone resorption (Soriano, P., C. Montgomery, R. Geske, and A. Bradley. 1991. Cell. 64:693-702), demonstrating a critical functional role of pp60c-src in osteoclast activity. Since decreased bone resorption could result from a defect either within the osteoclast or within other cells present in its environment, indirectly affecting osteoclast functions, we determined which cell(s) in bone expressed high levels of pp60c-src Measuring pp60c-src protein and kinase activities in osteoclasts and immunolocalizing pp60c-src in bone, we find that expression of pp60c-src is nearly as high in osteoclasts as in brain and platelets. In contrast, other bone cells contain only very low levels of the protein. In addition, expression of the c-src gene product increases when bone marrow cells are induced to express an osteoclast-like phenotype by 1,25-dihydroxy-vitamin D3, further suggesting that high expression of pp60c-src is part of the osteoclast phenotype. Three other src-like kinases, c-fyn, c-yes, and c-lyn, are also expressed in osteoclasts at ratios to pp60c-src similar to what is found in platelets. These src-related proteins do not, however, compensate for the absence of pp60c-src in the src- mice, thereby suggesting that pp60c-src may have a specific function in osteoclasts. Although further work is necessary to elucidate what the critical role of pp60c-src in osteoclasts is, our observation that the protein is associated mostly with the membranes of intracellular organelles suggests the possibility that this role might be at least in part related to the targeting or fusion of membrane vesicles.

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Section: Discussionmentioning

confidence: 99%

Osteoclasts express high levels of pp60c-src in association with intracellular membranes.

Horne

Neff

Chatterjee

et al. 1992

The Journal of Cell Biology

213

135

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“…Interestingly, MMP-14 is concentrated either at the leading edge of migrating osteoclasts, or at the sealing zone of polarized osteoclasts organized for resorption (Irie et al, 2001;Sato et al, 1997). MMP-14 immunoreactivity co-localizes with podosomes , specialized membrane protrusions establishing close-contact-like adhesions (Aubin, 1992;Baron et al, 1993;Marchisio et al, 1984). The importance of MMP activity for podosome function is further shown by the demonstrations (1) that an MMP inhibitor increases the life-span of podosomes in osteoclasts thereby inhibiting their migration (Goto et al, 2002), (2) that MMP-14 is involved in the processing of the ␣ v subunit of the ␣ v ␤ 3 integrin, which is an important component of the podosome, and that this processing stimulates migration of breast carcinoma cells (Deryugina et al, 2002).…”

Section: Mmp-9 and Mmp-14 Appear The Critical Mmpsmentioning

confidence: 98%

Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities

Delaissé

Andersen

Engsig

et al. 2003

Microscopy Res & Technique

287

184

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The best established proteolytic event of osteoclasts is bone matrix solubilization by the cysteine proteinase cathepsin K. Here, however, we draw the attention on osteoclastic activities depending on matrix metalloproteinases (MMPs). We discuss the observations supporting that MMPs contribute significantly to bone matrix solubilization in specific areas of the skeleton and in some developmental and pathological situations. Our discussion takes into account (1) the characteristics of the bone remodeling persisting in the absence of cathepsin K, (2) the ultrastructure of the resorption zone in response to inactivation of MMPs and of cathepsin K in different bone types, (3) bone resorption levels in MMP knockout mice compared to wild-type mice, (4) the identification of MMPs in osteoclasts and surrounding cells, and (5) the effect of different bone pathologies on the serum concentrations of specific collagen fragments believed to discriminate between cathepsin K and MMP cleavage. Next, we provide evidence that MMPs are very critical for osteoclast migration, thereby controlling also the cell-matrix interactions required for cell attachment/detachment. The evidence supporting this role is based on a model of osteoclast recruitment in primitive long bones, an assay of osteoclast invasion through collagen gel, and the effect of proteinase inhibitors/knockouts in these models. Furthermore, we mention observations indicating a role of MMPs in initiation of bone resorption. Finally, we emphasize the many distinct ways MMPs may alter focally the extracellular environment thereby regulating the osteoclast behavior. Although the understanding of MMPs in osteoclast biology is rapidly expanding, it is suspected that important roles remain to be discovered.

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“…3C, arrow). [Ruffled borders are specialized membranous areas of the osteoclast, which allow it to attach to the bone matrix and secrete hydrogen ions and digestive enzymes that resorb bone (Baron et al 1993). ] However, even the attached osteoclasts appeared unable to resorb significant amounts of bone (Fig.…”

Section: Traf6-deficient Mice Are Osteopetroticmentioning

confidence: 99%

TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling

Lomaga¹,

Yeh²,

Sarosi³

et al. 1999

Genes & Development

1,180

927

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Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.

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Biology of the Osteoclast

Cited by 26 publications

References 130 publications

Osteoclasts express high levels of pp60c-src in association with intracellular membranes.

Osteoclasts express high levels of pp60c-src in association with intracellular membranes.

Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities

TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling

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