Plasmin-Mediated Proteolysis of Osteocalcin

Novak, Josef F.; Hayes, Niall; Nishimoto, Satoru K.

doi:10.1359/jbmr.1997.12.7.1035

Cited by 38 publications

(37 citation statements)

References 42 publications

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“…The C-terminal pentapeptide FYGPV and an octapeptide were found to have chemotactic activity to osteoclast precursor cells (11,58). Previous studies have shown that plasmin, which is associated with osteoblast membranes, cleaves osteocalcin at the C-terminal between residues 43 and 44, arg-arg (or lys-arg), producing two peptides comprising residues 1-43 and 44-49 (59). Figure (6B) shows the osteocalcin structure in the bone binding orientation, and it is clear that the C-terminus extends outward and would be accessible to neighboring cells as well as endogenous proteinases.…”

Section: Discussionmentioning

confidence: 91%

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

Dowd

Rosen

et al. 2003

Biochemistry

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Structural information on osteocalcin or other noncollagenous bone proteins is very limited. We have solved the three-dimensional structure of calcium bound osteocalcin using 1 H 2D NMR techniques and proposed a mechanism for mineral binding. The protons in the 49 amino acid sequence were assigned using standard two-dimensional homonuclear NMR experiments. Distance constraints, dihedral angle constraints, hydrogen bonds, and 1 H and 13 C chemical shifts were all used to calculate a family of 13 structures. The tertiary structure of the protein consisted of an unstructured N terminus and a C-terminal loop (residues 16-49) formed by long-range hydrophobic interactions. Elements of secondary structure within residues 16-49 include type III turns (residues 20-25) and two α-helical regions (residues 27-35 and 41-44). The three Gla residues project from the same face of the helical turns and are surface exposed. The genetic algorithm-molecular dynamics simulation approach was used to place three calcium atoms on the NMR-derived structure. One calcium atom was coordinated by three side chain oxygen atoms, two from Asp30, and one from Gla24. The second calcium atom was coordinated to four oxygen atoms, two from the side chain in Gla 24, and two from the side chain of Gla 21. The third calcium atom was coordinated to two oxygen atoms of the side chain of Gla17. The best correlation of the distances between the uncoordinated Gla oxygen atoms is with the intercalcium distance of 9.43 Å in hydroxyapatite. The structure may provide further insight into the function of osteocalcin.The family of vitamin K-dependent γ-carboxylated calcium binding proteins is important in a variety of tissues and cellular functions. The formation of γ-carboxyglutamic acid (Gla) 1 in the liver derived blood clotting factors, for example, results in calcium-dependent conformational changes in the proteins and functionally important interactions with acidic phospholipid surfaces (1-3). The predominant Gla protein found in bone matrix is † Support for this project was provided by NIH Grant ES-02030 to T.D., support from the Division of Environmental Sciences,Children's Hospital at Montefiore (CHAM), at the Albert Einstein College of Medicine to T.D., and NIH Grant AR-38460 to C.G. *Corresponding author. Address: Montefiore Medical Center, Moses Bldg. Rm. 401, 111 East 210th Street, Bronx, NY, 10467. Phone: 718-920-2276. Fax: 718-920-4377. dowd@aecom.yu.edu. 1 Abbreviations: Gla, γ-carboxyglutamic acid; Fmoc, 9-flourenyl-methyloxycarbonyl; CD, circular dichroism; NMR, nuclear magnetic resonance; HSQC, heteronuclear single-quantum correlation; NOE, nuclear Overhauser effect; NOESY, NOE spectroscopy; rmsd, root-mean-square deviation; TOCSY, total correlation spectroscopy. HHS Public Access Author manuscriptBiochemistry. Author manuscript; available in PMC 2015 July 28. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript osteocalcin (4, 5), a small Ca 2+ binding protein containing three Gla residues which are thought to facil...

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Section: Discussionmentioning

confidence: 91%

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

Dowd

Rosen

et al. 2003

Biochemistry

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“…Plasmin can activate transforming growth factor ␤ and release insulinlike growth factor from bone matrix, which may then independently stimulate osteoblast proliferation and activity. 60,61 In vitro, plasmin can cleave osteocalcin, 62 which is a bone-specific protein important for recruitment of osteoclasts and osteoblasts. 63,64 Osteoblasts express tPA, uPA, PA inhibitor 1, and a cellular receptor for uPA.…”

Section: Discussionmentioning

confidence: 99%

Plasmin Is Essential in Preventing Periodontitis in Mice

Sulniute

Lindh

Wilczyńska

et al. 2011

The American Journal of Pathology

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Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue-and urokinase-type plasminogen activators, developed periodontal disease similar to that in Plg-deficient mice; however, mice lacking only tissueor urokinase-type plasminogen activator remained healthy. Supplementation by injection of Plg-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Plg-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases.

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“…Because bone hydroxyapatite is able to absorb only intact OC molecules but not OC fragments (40,41 ), circulating intact OC, whether released from biosynthesis in osteoblasts or derived from resorption, may traffic back to the skeleton. Circulating intact OC, which is not adsorbed to hydroxyapatite, and the largest OC fragments are likely to be degraded by proteases in the circulation or peripheral organs (11,42 ).…”

Section: Discussionmentioning

confidence: 99%

Urinary Osteocalcin as a Marker of Bone Metabolism

et al. 2005

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Background: Osteocalcin (OC) is produced by osteoblasts during bone formation, and circulating OC has been used in clinical investigations as a marker of bone metabolism. OC is excreted into urine by glomerular filtration and can be found in urine as midmolecule fragments. Methods: We developed and evaluated three immunoassays (U-MidOC, U-LongOC, and U-TotalOC) for the detection of various molecular forms of urine OC (U-OC). We evaluated the association of U-OC with other markers of bone turnover and with bone mass in 1044 elderly women and studied seasonal and circadian variation of U-OC. Results: U-OC correlated with other bone turnover markers [Spearman correlation (r), 0.30 -0.57; P <0.0001], demonstrating the association between U-OC and skeletal metabolism. There was also a significant association between bone metabolism assessed by U-OC quartiles and bone mass assessed by total body bone mineral content (P <0.0001). The seasonal effects appeared to be rather small, but we observed a significant circadian rhythm similar to the one reported for serum OC with high values in the morning and low values in the afternoon. Conclusions: The three immunoassays had unique specificities toward different naturally occurring U-OC fragments. U-OC concentrations measured with any of these assays correlated with bone turnover rates assessed by conventional serum markers of bone metabolism. The measurement of OC in urine samples could be used as an index of bone turnover in monitoring bone metabolism.

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Plasmin-Mediated Proteolysis of Osteocalcin

Cited by 38 publications

References 42 publications

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

Plasmin Is Essential in Preventing Periodontitis in Mice

Urinary Osteocalcin as a Marker of Bone Metabolism

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Plasmin-Mediated Proteolysis of Osteocalcin

Cited by 38 publications

References 42 publications

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using 1H NMR Spectroscopy

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using 1H NMR Spectroscopy

Plasmin Is Essential in Preventing Periodontitis in Mice

Urinary Osteocalcin as a Marker of Bone Metabolism

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The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy

The Three-Dimensional Structure of Bovine Calcium Ion-Bound Osteocalcin Using ¹H NMR Spectroscopy