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PubMed2001

Impaired wound healing in mice deficient in a matricellular protein SPARC (osteonectin, BM-40).

BACKGROUND: SPARC is a matricellular protein involved in cell-matrix interactions. From expression patterns at the wound site and in vitro studies, SPARC has been implicated in the control of wound healing. Here we examined the function of SPARC in cutaneous wound healing using SPARC-null mice and dermal fibroblasts derived from them. RESULTS: In large (25 mm) wounds, SPARC-null mice showed a significant delay in healing as compared to wild-type mice (31 days versus 24 days). Granulation tissue formation and extracellular matrix protein production were delayed in small 6 mm SPARC-null wounds initially but were resolved by day 6. In in vitro wound-healing assays, while wild-type primary dermal fibroblasts showed essentially complete wound closure at 11 hours, wound closure of SPARC-null cells was incomplete even at 31 hours. Addition of purified SPARC restored the normal time course of wound closure. Treatment of SPARC-null cells with mitomycin C to analyze cell migration without cell proliferation showed that wound repair remained incomplete after 31 hours. Cell proliferation as measured by 3H-thymidine incorporation and collagen gel contraction by SPARC-null cells were not compromised. CONCLUSIONS: A significant delay in healing large excisional wounds and setback in granulation tissue formation and extracellular matrix protein production in small wounds establish that SPARC is required for granulation tissue formation during normal repair of skin wounds in mice. A defect in wound closure in vitro indicates that SPARC regulates cell migration. We conclude that SPARC plays a role in wound repair by promoting fibroblast migration and thus granulation tissue formation.

Animals↗
PubMed1988

Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane.

The identification and cDNA cloning of bone-enriched osteonectin and parietal endoderm-enriched SPARC indicated that these proteins share greater than 90% homology. The present study reports substantial expression of this Mr 43,000 protein in human decidua and carcinoma. Metabolic labeling of human decidua tissue in organ culture demonstrated significant osteonectin biosynthesis. Further, Northern analysis and in situ hybridization showed that the osteonectin mRNA level in human decidua is very high. Immunohistochemically, the large mature decidual cells exhibited faint cytoplasmic immunoreactivity with antibodies to osteonectin and a distinct immunoreactivity of the newly deposited basement membranes encircling these cells. The intermediate-sized decidual cells exhibited a strong cytoplasmic immunostaining with antibodies to osteonectin. The small elongated stromal cells were devoid of osteonectin immunoreactivity. Blood vessels exhibited variable positive immunoreactivity. The osteonectin expression in 38 cases of human carcinomas was examined. In well-differentiated carcinomas osteonectin immunoreactivity was located in the basement membrane area, codistributing with laminin. Cytoplasmic osteonectin immunoreactivity was found in poorly differentiated carcinomas. Stromal cells in the peritumoral tissue and some vessels were immunoreactive. Using in situ hybridization, it appeared that both the tumor cells and the stromal cells contained osteonectin transcripts. In normal steady state human nonosseus tissues investigated, osteonectin was found inconsistently in the basement membranes only, as based on the present immunohistochemical technique. These results suggest that the osteonectin/SPARC gene appears activated in certain human tissues characterized by de novo formation of basement membrane.

Animals↗
PubMed2005

Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis.

Skeletal metastases occur with high incidence in patients with breast cancer and cause long-term skeletal morbidity. Osteonectin (SPARC, BM-40) is a bone matrix factor that is an in vitro chemoattractant for breast and prostate cancer cells. Increased expression of osteonectin is found in malignant breast tumors. We infected MDA-231 breast cancer cells with an adenovirus expressing osteonectin to examine the role of osteonectin expression in breast cancer cells and its effect on metastasis, in particular to bone. Expression of osteonectin did not affect MDA-231 cell proliferation, apoptosis, migration, cell aggregation, or protease cleavage of collagen IV. However, in vitro invasion of these osteonectin-infected cells through Matrigel and colony formation on Matrigel was decreased. Interestingly, high osteonectin expression in MDA-231 cells inhibited metastasis in a dose-dependent manner to many different organs including bone. The reduction in metastasis may be due to decreased platelet-tumor cell aggregation, because exogenous osteonectin inhibited platelet aggregation in vitro and the high osteonectin expression in MDA-231 cells reduced tumor cell-induced thrombocytopenia in vivo compared with control-infected cells. These studies suggest that high endogenous expression of osteonectin in breast cancer cells may reduce metastasis via reduced invasive activity and reduced tumor cell-platelet aggregation.

Adenoviridae↗
PubMed1984

An osteonectinlike protein in porcine periodontal ligament and its synthesis by periodontal ligament fibroblasts.

Periodontal ligament, a soft connective tissue that lies between cementum and alveolar bone in the periodontium, has been shown to contain an osteonectinlike protein. The similarity between porcine ligament osteonectin and bovine bone osteonectin was evident from immunochemical studies, from migration characteristics on sodium dodecyl sulfate - polyacrylamide gel electrophoresis (SDS-PAGE) and from binding studies on hydroxyapatite. Using immunotransfer and immunodot analyses, ligament osteonectin was found to be extractable from tissues with 4 M guanidine-HCl (GuHCl) and 4 M GuHCl - 0.5 M EDTA and to comigrate with authentic bovine osteonectin on SDS-PAGE with a relative mass approximately 38 000. Furthermore, osteonectin from guanidine extracts of ligament was bound to hydroxyapatite in the presence of 4 M GuHCl. Immunofluorescence studies showed the osteonectin to be distributed throughout the extracellular matrix of the ligament and to be present within the ligament fibroblasts in a perinuclear, punctate distribution. Biosynthesis of osteonectin by ligament fibroblasts was studied following pulse-chase labelling with [35S]methionine and immunoprecipitation. The labelled osteonectin in the chased culture medium represented approximately 0.5% of the total labelled proteins secreted. It comigrated on SDS-PAGE with the corresponding labelled protein from pulsed cells and with the protein extracted from the tissue.

Animals↗
PubMed1989

Separation of bone matrix proteins by calcium-induced precipitation.

It was found that significant precipitation occurred immediately after calcium, at a concentration as low as 2 mM, was added to a desalted solution of EDTA extract of adult bovine femur. The maximal yield of the precipitates was observed at a calcium concentration of 30 mM. These precipitates were dissolved in 0.5 M EDTA, desalted, and characterized by Sepharose CL-6B gel filtration chromatography and high performance gel-exclusion chromatography. Results revealed that the precipitates were enriched in a 40 K protein and a higher molecular weight fraction as compared with the original extract of bone proteins. The 40 K fraction was isolated and identified as osteonectin, as judged from amino acid analysis, electrophoresis, and immunodetection. The supernatant after calcium-induced precipitation predominantly contained osteocalcin and a 50 K protein that was tentatively identified as alpha 2HS protein. Osteonectin was purified from the calcium-induced precipitates from the EDTA extract of bovine bone. By calcium titration using fluorescence spectrometry, the isolated osteonectin showed high affinity to calcium ions with an apparent dissociation constant (K0.5) of 8 x 10(-7) M. Thus, the use of calcium to separate bone proteins, especially osteonectin, was proved to be a useful technique. In addition, calcium-induced precipitation of osteonectin suggested a possible in vivo mechanism via which osteonectin might interact with calcium ions and participate in the initial immobilization of calcium to induce the nucleation of calcification in bone tissue.

Animals↗
PubMed2001

Regional and cellular localization of osteonectin/SPARC expression in connective tissue and cytotrophoblastic layers of human fetal membranes at term.

Fetal membranes overlying the cervix in patients prior to and during labour, and within the rupture tear after spontaneous delivery at term, exhibit altered morphology. In this study we report that in comparison to mid-zone fetal membranes biopsies, these regions are characterized by increased expression of the matricellular protein osteonectin or SPARC (Secreted Protein Acidic and Rich in Cysteine). In the reticular layer, the percentage of vimentin positive mesenchymal cells immunoreactive for osteonectin increased in these regions from 3-4% to 25-33% and represented a fraction of the alpha-smooth muscle actin positive myofibroblasts elevated in the same regions. In the fibroblastic layer, the percentage of osteonectin positive cells increased from 1-5% to 8-13%; however, these did not exhibit the same relationship to the alpha-smooth muscle actin positive myofibroblasts in this layer. In the cytotrophoblastic layer the percentage of cytotrophoblastic cells immunoreactive for osteonectin increased from 1% to 6-12%. Elevation of in-situ detectable mRNA was also observed in the same cellular populations in this region. The incidence of cells positive for osteonectin mRNA or protein in the reticular layer correlated with morphological changes. Osteonectin has been implicated in the regulation of extracellular matrix turnover, and its pattern of expression suggests a role in the regional connective tissue and cytotrophoblastic changes proposed to be involved in the cleavage and rupture of fetal membranes.

Connective Tissue↗
PubMed1997

Serum bone alkaline phosphatase is superior to plasma levels of bone matrix proteins for assessment of bone metabolism in patients receiving renal transplants.

The plasma concentrations of two bone matrix proteins (osteocalcin, osteonectin) were monitored in 56 samples from 14 patients receiving renal transplants and the values compared with serum bone alkaline phosphatase mass concentrations and osteotropic hormone levels (parathyroid hormone, calcitriol). There were no significant changes in the concentrations of plasma osteonectin at any time after transplantation, as compared with the values before transplantation (P > 0.1). None of the plasma samples showed osteonectin levels above the reference interval. There was a weak but significant relationship between platelet counts and plasma osteonectin levels (r = +0.322; P < 0.05). Osteocalcin showed a marked decrease of the values 1 week following transplantation as compared with the values before transplantation without further change of the values 1 and 3 months after transplantation (P > 0.5) whereas 3 months after transplantation bone alkaline phosphatase levels were higher than before transplantation (P < 0.05). Multiple regression analysis (performed with data from 42 samples obtained after transplantation) revealed serum creatinine as an independent predictor of plasma osteocalcin whereas serum calcitriol was an independent predictor of serum bone alkaline phosphatase (P < 0.05). No correlation was observed between serum calcitriol/plasma parathyroid hormone on the one hand and plasma osteocalcin on the other (P > 0.05). After transplantation there was a lack of correlation between serum bone alkaline phosphatase mass concentrations and plasma osteocalcin values (P > 0.05). In conclusion, serum bone alkaline phosphatase should be preferred to bone matrix proteins for the assessment of bone metabolism in patients receiving renal transplants: (a) bone alkaline phosphatase-but not osteocalcin-is significantly correlated with calcitriol and adequately reflects increased bone formation after renal transplantation; (b) interpretation of osteocalcin values is severely hampered by their strong correlation with serum creatinine concentrations; (c) plasma osteonectin determinations are not useful for monitoring bone formation.

Adult↗
PubMed1999

Noncollagenous bone matrix proteins, calcification, and thrombosis in carotid artery atherosclerosis.

Advanced atherosclerosis is often associated with dystrophic calcification, which may contribute to plaque rupture and thrombosis. In this work, the localization and association of the noncollagenous bone matrix proteins osteonectin, osteopontin, and osteocalcin with calcification, lipoproteins, thrombus/hemorrhage (T/H), and matrix metalloproteinases (MMPs) in human carotid arteries from endarterectomy samples have been determined. According to the recent American Heart Association classification, 6 of the advanced lesions studied were type V (fibroatheroma) and 16 type VI (complicated). Osteonectin, osteocalcin, and osteopontin were identified by monoclonal antibodies IIIA(3)A(8), G12, and MPIIIB10(1) and antiserum LF-123. Apolipoprotein (apo) AI, B, and E; lipoprotein(a); fibrinogen; fibrin; fragment D/D-dimer; MMP-2 (gelatinase A); and MMP-3 (stromelysin-1) were identified with previously characterized antibodies. Calcium phosphate deposits (von Kossa's stain) were present in 82% of samples (3 type V and 15 type VI). Osteonectin was localized in endothelial cells, SMCs, and macrophages and was associated with calcium deposits in 33% of type V and 88% of type VI lesions. Osteopontin was distributed similarly to osteonectin and was associated with calcium deposits in 50% of type V and 94% of type VI lesions. Osteocalcin was localized in large calcified areas only (in 17% of type V and 38% of type VI lesions). ApoB colocalized with cholesterol crystals and calcium deposits. Lipoprotein(a) was localized in the intima, subintima, and plaque shoulder. Fibrin (T/H) colocalized with bone matrix proteins in 33% of type V and 69% of type VI lesions. MMP-3 was cytoplasmic in most cells and colocalized with calcium and fibrin deposits. MMP-2 was less often associated with calcification. The results of this study show that osteonectin, osteopontin, and osteocalcin colocalized with calcium deposits with apoB, fibrin, and MMP-3 in advanced, symptomatic carotid lesions. These data suggest that the occurrence of T/H might contribute to dystrophic arterial calcification in the progression and complications of atherosclerosis.

Arteriosclerosis↗
PubMed2001

Temporal and spatial gene expression of major bone extracellular matrix molecules during embryonic mandibular osteogenesis in rats.

It is not known how gene expression of bone extracellular matrix molecules is controlled temporally and spatially, or how it is related with morphological differentiation of osteoblasts during embryonic osteogenesis in vivo. The present study was designed to examine gene expressions of type I collagen, osteonectin, bone sialoprotein, osteopontin, and osteocalcin during mandibular osteogenesis using in situ hybridization. Wistar rat embryos 13-20 days post coitum were used. The condensation of mesenchymal cells was formed in 14-day rat embryonic mandibles and expressed genes of pro-alpha 1 (I) collagen, osteonectin, bone sialoprotein and osteopontin. Cuboidal osteoblasts surrounding the uncalcified bone matrix were seen as early as in 15-day embryonic mandibles, while flat osteoblasts lining the surface of the calcified bone were seen from 16-day embryonic mandibles. Cuboidal osteoblasts expressed pro-alpha 1(I) collagen, osteonectin and bone sialoprotein intensely but osteopontin very weakly. In contrast, flat osteoblasts expressed osteopontin very strongly. Osteocytes expressed the extracellular matrix molecules actively, in particular, osteopontin. The present study demonstrated the distinct gene expression pattern of type I collagen, osteonectin, bone sialoprotein, osteopontin and osteocalcin during embryonic mandibular osteogenesis in vivo.

Animals↗