Removal of Osteoclast Bone Resorption Products by Transcytosis

Salo, Jari; Lehenkari, Petri; Mulari, Mika; Metsikkö, Kalervo; Väänänen, H. Kalervo

doi:10.1126/science.276.5310.270

Cited by 382 publications

(231 citation statements)

References 19 publications

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“…Indeed, incubating osteocalcin for 2 weeks at 378C at pH 4.5 was sufficient to decrease its decarboxylation and to confer to it the ability to stimulate insulin secretion. (3) These results are consistent with previous studies by Salo and colleagues, (10) who demonstrated that osteocalcin was found in the vicinity of the osteoclast resorption lacunae and was released by these cells during bone resorption. Additional confirmation of the importance of bone resorption in decarboxylating osteocalcin was provided by a bone marrow transplantation experiment in which bone marrow hematopoietic stem cells from a mouse with osteopetrosis (oc/oc) conferred to otherwise wild-type mice an osteopetrotic phenotype, a glucose-intolerance phenotype, and also led to a substantial decrease in the amount of undercarboxylated osteocalcin when measured through a new ELISA.…”

Section: Insulin Signaling In Osteoblasts Bone Resorption and Osteosupporting

confidence: 91%

The osteoblast: An insulin target cell controlling glucose homeostasis

Clemens

Karsenty

2010

Journal of Bone and Mineral Research

246

179

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The past five years have witnessed the emergence and discovery of unexpected functions played by the skeleton in whole-organism physiology. Among these newly described tasks is the role of bone in the control of energy metabolism, which is achieved through the secretion of osteocalcin, an osteoblasts-derived hormone regulating insulin secretion, insulin sensitivity, and energy expenditure. These initial findings raised several fundamental questions on the nature of insulin action in bone. Discoveries made independently by our two groups have provided answers recently to some of these questions. Through the analysis of mice lacking insulin receptor (InsR) only in osteoblasts, we found that insulin signaling in these cells favors whole-body glucose homeostasis. Importantly, this function of insulin signaling in osteoblasts was achieved through the negative regulation of osteocalcin carboxylation and bioavailability. Our studies also established that insulin signaling in osteoblasts was a positive regulator not only of postnatal bone acquisition but also of bone resorption. Interestingly, it appears that insulin signaling in osteoblasts induced osteocalcin activation by stimulating osteoclast activity. Indeed, the low pH generated during bone resorption is a sufficient means to decarboxylate osteocalcin. Our findings establish that the osteoblast is an important target used by insulin to control whole-body glucose homeostasis and identify bone resorption as the mechanism regulating osteocalcin activation. ß

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Section: Insulin Signaling In Osteoblasts Bone Resorption and Osteosupporting

confidence: 91%

The osteoblast: An insulin target cell controlling glucose homeostasis

Clemens

Karsenty

2010

Journal of Bone and Mineral Research

246

179

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“…Organic bone matrix degradation is mediated by proteolytic enzymes, primarily cathepsin K, and the released material is endocytosed for further degradation in transcytotic vesicles in the resorbing osteoclast. Eventually, the degraded material is excreted into the extracellular space via a functional secretory domain (24,25). Because osteocalcin is rather susceptible to proteolysis in vitro (16,26), acids and proteases may also attack osteocalcin during bone degradation.…”

Section: Osteocalcin (Oc)mentioning

confidence: 99%

Release of Intact and Fragmented Osteocalcin Molecules from Bone Matrix during Bone Resorption in Vitro

Ivaska

Hentunen

Vääräniemi

et al. 2004

Journal of Biological Chemistry

178

114

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Osteocalcin detected from serum samples is considered a specific marker of osteoblast activity and bone formation rate. However, osteocalcin embedded in bone matrix must also be released during bone resorption. To understand the contribution of each type of bone cell in circulating osteocalcin levels, we used immunoassays detecting different molecular forms of osteocalcin to monitor bone resorption in vitro. Osteoclasts were obtained from rat long bones and cultured on bovine bone slices using osteocalcin-depleted fetal bovine serum. In addition, human osteoclasts differentiated from peripheral blood mononuclear cells were used. Both rat and human osteoclasts released osteocalcin from bovine bone into medium. The amount of osteocalcin increased in the presence of parathyroid hormone, a stimulator of resorption, and decreased in the presence of bafilomycin A1, an inhibitor of resorption. The amount of osteocalcin in the medium correlated with a well characterized marker of bone resorption, the C-terminal telopeptide of type I collagen (r > 0.9, p < 0.0001). The heterogeneity of released osteocalcin was determined using reverse phase high performance liquid chromatography, and several molecular forms of osteocalcin, including intact molecule, were identified in the culture medium. In conclusion, osteocalcin is released from the bone matrix during bone resorption as intact molecules and fragments. In addition to the conventional use as a marker of bone formation, osteocalcin can be used as a marker of bone resorption in vitro. Furthermore, bone matrix-derived osteocalcin may contribute to circulating osteocalcin levels, suggesting that serum osteocalcin should be considered as a marker of bone turnover rather than bone formation. Osteocalcin (OC)1 is a 6-kDa noncollagenous protein produced by osteoblasts (1), osteocytes (2), and odontoblasts (3).Osteocalcin messenger RNA has also been detected in tissues other than bone, but it appears to be processed properly only in the bone microenvironment (4, 5). The structure of osteocalcin is characterized by three glutamic acid residues, which undergo a vitamin K-dependent carboxylation. The ␥-carboxyglutamic acid residues (Gla) provide osteocalcin with the ability to bind bone hydroxyapatite with a high affinity (6, 7). Osteocalcin is the second most abundant protein in the bone matrix, and it is highly conserved among all vertebrate species (8). The biological function of osteocalcin is probably related to the regulation of bone turnover and/or mineralization (9, 10).The expression of osteocalcin is a marker of late osteoblast differentiation and is induced only after the expression of other osteoblastic markers such as alkaline phosphatase and type I collagen (11,12). Newly synthesized osteocalcin is mostly (60 -90%) adsorbed to the bone hydroxyapatite via the Gla residues, but a part of it leaks into the circulation where it can be detected (13,14). Although osteoblasts synthesize only intact osteocalcin (15), osteocalcin may further undergo intracellular processing or ...

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“…The acidic pH of the lacunae (3,4) is essential for mineral solubilization and hydrolysis of bone matrix by enzymes, including collagenase and cathepsin K (5). The degraded matrix is transported in luminal acidic vesicles (organelles) to the secretory domain facing the extracellular space (6). Vacuolar type H ϩ -ATPase (V-ATPase) 1 functions in the ruffled border as a proton pump that acidifies the resorption lacunae.…”

mentioning

confidence: 99%

From Lysosomes to the Plasma Membrane

Toyomura

Murata

Yamamoto

et al. 2003

Journal of Biological Chemistry

255

121

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Osteoclasts generate a massive acid flux to mobilize bone calcium. Local extracellular acidification is carried out by vacuolar type H ؉ -ATPase (V-ATPase) localized in the plasma membrane. We have shown that a3, one of the four subunit a isoforms (a1, a2, a3, and a4), is a component of the plasma membrane V-ATPase (Toyomura, T., Oka, T., Yamaguchi, C., Wada, Y., and Futai, M. (2000) J. Biol. Chem. 275, 8760 -8765). To establish the unique localization of V-ATPase, we have used a murine macrophage cell line, RAW 264.7, that can differentiate into multinuclear osteoclast-like cells on stimulation with RANKL (receptor activator of nuclear factor B ligand). The V-ATPase with the a3 isoform was localized to late endosomes and lysosomes, whereas those with the a1 and a2 isoforms were localized to organelles other than lysosomes. After stimulation, the V-ATPase with the a3 isoform was immunochemically colocalized with lysosome marker lamp2 and was detected in acidic organelles. These organelles were also colocalized with microtubules, and the signals of lamp2 and a3 were dispersed by nocodazole, a microtubule depolymerizer. In RAW-derived osteoclasts cultured on mouse skull pieces, the a3 isoform was transported to the plasma membrane facing the bone and accumulated inside podosome rings. These findings indicate that V-ATPases with the a3 isoform localized in late endosomes/lysosomes are transported to the cell periphery during differentiation and finally assembled into the plasma membrane of mature osteoclasts.Osteoclasts are multinuclear bone-resorbing cells derived from hematopoietic stem cells (1, 2) that form an extracellular compartment (resorption lacunae) between the plasma membrane (ruffled border) and the bone surface. The acidic pH of the lacunae (3, 4) is essential for mineral solubilization and hydrolysis of bone matrix by enzymes, including collagenase and cathepsin K (5). The degraded matrix is transported in luminal acidic vesicles (organelles) to the secretory domain facing the extracellular space (6). Vacuolar type H ϩ -ATPase (V-ATPase) 1 functions in the ruffled border as a proton pump that acidifies the resorption lacunae. Although the important role of V-ATPase in bone resorption has been established, much less is known about the mechanism of targeting the enzyme during osteoclast differentiation. Meanwhile, V-ATPases function in the membranes of ubiquitous organelles, including secretory vesicles, endosomes, the Golgi apparatus, and lysosomes. Thus, it is of interest to know how V-ATPases are localized to the various membranes and whether or not they have different compositions depending on the cellular location (7).V-ATPase is a multisubunit complex formed from a catalytic V 1 sector and a membrane-spanning V O sector (7-13). The V O sector may have a pertinent role in localizing V-ATPases to various cellular membranes. The yeast V O sector is composed of five subunits (a, c, cЈ, cЉ, and d) and has two subunit a isoforms, Stv1p and Vph1p. The nematode Caenorhabditis elegans has two c (14 -16) ...

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Removal of Osteoclast Bone Resorption Products by Transcytosis

Cited by 382 publications

References 19 publications

The osteoblast: An insulin target cell controlling glucose homeostasis

The osteoblast: An insulin target cell controlling glucose homeostasis

Release of Intact and Fragmented Osteocalcin Molecules from Bone Matrix during Bone Resorption in Vitro

From Lysosomes to the Plasma Membrane

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