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PubMed2002

[Effects of simulated weightlessness on the expression of cyclooxygenase-2 in rat calvarial osteoblasts induced by fluid shear stress].

OBJECTIVE: To investigate the effect of simulated weightlessness on mechanotransduction in rat calvarial osteoblasts. METHOD: Osteoblasts were isolated from neonatal rat calvariae and then were set to two groups. One was cultured in clinostat to simulate the weightlessness environment. Another was cultured in 1 G gravitational environment. After 60 h, osteoblasts were treated with 0.5 Pa or 1.5 Pa FSS in a flow chamber. The FSS treatment time was set to 30 min and 60 min, respectively. The specimens of each group were obtained for immunohistochemistry staining and determination of expressions of cyclooxygenase-2 (COX-2) in osteoblasts. RESULT: In osteoblasts cultured in 1 G gravitational environment, COX-2 expression was increased remarkably from 30 min to 60 min with the treatment of FSS (P<0.01). There was no clear difference between the expression of COX-2 after treatments of 0.5 Pa or 1.5 Pa FSS; In cells cultured in simulated weightlessness environment, no detectable expression of COX-2 was found with the treatment of 0.5 Pa FSS. The expression of COX-2 was only detected after 60 min treatment of 1.5 Pa FSS, but the level of expression was decreased significantly (P<0.01). CONCLUSION: These results demonstrated that the mechanotransduction in osteoblasts was down-regulated in simulated (correction of stimulated) weightlessness.

Animals↗

PubMed2002

Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures.

Fibroblast growth factor receptor (FGFR) signalling is important in the initiation and regulation of osteogenesis. Although mutations in FGFR1, 2, and 3 genes are known to cause skeletal deformities, the expression of FGFR4 in bony tissue remains unclear. We have investigated the expression pattern of FGFR4 in the neonatal mouse calvaria and compared it to the expression pattern in cultures of primary osteoblasts. Immunohistochemistry demonstrated that FGFR4 was highly expressed in rudimentary membranous bone and strictly localised to the cellular components (osteoblasts) between the periosteal and endosteal layers. Cells in close proximity to the newly formed osteoid (preosteoblasts) also expressed FGFR4 on both the endosteal and periosteal surfaces. Immunocytochemical analysis of primary osteoblast cultures taken from the same cranial region also revealed high levels of FGFR4 expression, suggesting a similar pattern of cellular expression in vivo and in vitro. RT-PCR and Western blotting for FGFR4 confirmed its presence in primary osteoblast cultures. These results suggest that FGFR4 may be an important regulator of osteogenesis with involvement in preosteoblast proliferation and differentiation as well as osteoblast functioning during intramembranous ossification. The consistent expression of FGFR4 in vivo and in vitro supports the use of primary osteoblast cultures for elucidating the role of FGFR4 during osteogenesis.

Animals↗

PubMed2002

[Biocompatibility of adult human osteoblasts with coral-derived hydroxyapatite in vitro].

OBJECTIVE: To study the biocompatibility of the osteoblasts from adult human bone marrow with coral-derived hydroxyapatite (CHA) in in vitro culture. METHODS: Bone marrow was obtained from healthy adult subjects and cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10 % fetal bovine serum. The subsequent cell passaging was conducted in conditioned medium containing dexamethasone, beta-sodium glycerophosphate and ascorbic acid, with the osteoblasts in culture then divided into CHA group (in which the cells were cultured with CHA) and osteoblasts group (without CHA). The proliferation and differentiation of all the cultured cells were observed at different time points under inverted phase contrast microscope, optical microscope with HE staining and scanning electron microscope respectively. Proliferation of the cultured cells were evaluated by MTT assay, and the activity of alkaline phosphatase and total micro-protein contents in these cultured osteoblasts were quantitatively detected. RESULTS: The osteoblasts from adult human bone marrow grow well in vitro, regardless of the presence of CHA, with biological and morphological characteristics similar to those of normal osteoblasts. CHA improved the adhesion, growth and proliferation of the cultured cells, showing no adverse effects on the cell functions. CONCLUSION: CHA is an optimal scaffold material for bone tissue engineering, which may potentially find clinical application for bone defect repair.

Adult↗

PubMed2000

[The modulation of type I collagen and its receptor system on biological characteristics of osteoblasts].

This paper addresses the question whether type I collagen-receptor system is necessary for the functional activity of osteoblasts. Through blocking type I collagen-receptor system by type I collagen antibody or integrin alpha 2 beta 1 antibody, the proliferation of osteoblasts was studied by cell count, the apoptosis was studied by flow cytometry, and the mRNA expressions of type I collagen, integrin alpha 2 beta 1 and osteocalcin were also detected by RT-PCR techniques. When type I collagen-receptor system was blocked, osteoblasts showed high apoptosis rate, lower growth kinetics and weak mRNA expression of type I collagen, integrin alpha 2 beta 1 and osteocalcin; the blocking effect was reversible. It suggests that type I collagen-receptor system is necessary for osteoblastic phenotype. The biomaterials for bone tissue engineering should be constructed according to the extracellular matrix of osteoblasts, which supply normal extracellular environment for osteoblasts.

Apoptosis↗

PubMed2003

Abnormalities in the replicative capacity of osteoblastic cells in the proximal femur of patients with osteonecrosis of the femoral head.

OBJECTIVE: Aseptic nontraumatic osteonecrosis (ON) of the femoral head is a painful disorder that often leads to femoral head collapse due to subchondral fracture. We postulated that alteration of osteoblast function might play a role in the pathophysiology of ON. We evaluated the ex vivo proliferation rate and differentiation capacity of osteoblasts derived from the intertrochanteric region of the femur and of the iliac crest of patients with ON of the femoral head and compared it with patients with hip osteoarthritis (OA). METHODS: We examined the function of osteoblastic cells in cultures derived from bone biopsies of the intertrochanteric region of the femur and of the iliac crest obtained from 13 patients with ON of the femoral head and 8 patients with hip OA. The replicative capacity was assessed by the proliferation rate in secondary culture. The phenotypic characterization was evaluated by the level of alkaline phosphatase activity, the sensitivity to 1,25 (OH)2 vitamin D3, and collagen synthesis. RESULTS: The replicative capacity of the osteoblastic cells of the intertrochanteric area of the femur in ON patients was significantly reduced compared to patients with OA. The capacity of differentiation, however, was not different between ON and OA patients. CONCLUSION: The replicative capacity of osteoblastic cells is significantly reduced in the femur of patients with ON. Our results confirm that altered osteoblastic function plays a role in the pathophysiology of ON of the femoral head.

Adult↗

PubMed2002

[The effects of the mechanical stress on the cytoskeleton filament F-actin of osteoblast-like cells in vitro].

OBJECTIVE: Mechanical stimulation alters cell's metabolism, but little is known about the effects of mechanical strain on the cytoskeleton of osteoblasts. This study was to investigate the changes of F-actin, a cytoskeleton protein of rat-derived osteoblast-like cell line UMR-106, and to provide theoretical basis for further investigation of mechanism of bone-remodeling. METHODS: Centrifugation was used to inflict UMR-106 the top-bottom axial stress (225 x g) expected and, confocal laser scanning microscope (LSCM) was used to examine the morphological changes 15, 30 min, and 1, 4, 6, 12, and 24 hr after undergoing physical strain. Unstrained cells were used as the controls respectively. The distribution of F-actin was observed after immunofluorescent staining and electronic photo was scanned for further analysis of osteoblasts' average fluorescence by spectrofluorimetric quantification. RESULTS: Except the 24 hr group, the actin filaments of the strained osteoblasts were much shorter, more flimsy and tenuous than that of untreated osteoblasts and unlike the normal distribution of bundles or membrane-like of the control group, and they were arranged without direction. Its quantified fluorescence was significantly less than that of the controls. But the 24 hr group showed a normal distribution and a stronger fluorescence. CONCLUSION: It is concluded that the cytoskeleton of the strained osteoblasts has a reduced number of F-actin fibers and a unique abnormal morphology and could recover in 24 hr.

Actins↗

PubMed2003

Modulation of isoflavones on bone-nodule formation in rat calvaria osteoblasts in vitro.

OBJECTIVE: To observe the effects of two main isoflavones, daidzein and genistein on the bone-nodule formation in rat calvaria osteoblasts in vitro. METHODS: Osteoblasts obtained from newborn Sprague-dawley rat calvaria were cultured for several generations. The second generation cells were cultured in Minimum Essential Medium supplemented with ascorbic acid and Na-beta-glycerophosphate for several days, in the presence of daidzein and genistein, with or without the estrogen receptor antagonist ICI 182780. Number of nodules was counted at the end of the incubation period (day 20) by staining with Alizarin Red S calcium stain. The release of osteocalcin, as a marker of osteoblast activity, was also determined on day 7 and day 12 during the incubation period. RESULTS: Compared with the control, the numbers of nodules were both increased by incubation with daidzein and genistein. 17 beta-estradiol was used as a positive control and proved to be a more effective inducer of the increase in bone-nodules formation that daidzein and genistein. The release of osteocalcin into culture media was also increased in the presence of daidzein and genistein, as well as 17 beta-estradiol on day 7 and day 12 (day 12 were higher). The estrogen receptor antagonist ICI 182780 completely blocked the genistein- and 17 beta-estradiol-induced increase of nodule numbers and osteocalcin release in osteoblasts. However, the effects induced by daidzein could not be inhibited by ICI 182780. CONCLUSION: These findings suggest that geinistein can stimulate bone-nodule formation and increase the release of osteocalcin in rat osteoblasts. The effects, like those induced by 17 beta-estradiol, are mediated by the estrogen receptor dependent pathway. Daidzein also can stimulate bone-nodule formation and increase the release of osteocalcin in rat osteoblasts, but it is not, at least not merely, mediated by the estrogen receptor dependent pathway.

Animals↗

PubMed2003

[Immunological research of rat osteoblast xenotransplantation].

OBJECTIVE: To detect the immunoreaction after osteoblast xenotransplantation and to investigate the possibility of heterogenic osteocyte transplantation and tissue engineered bone reconstruction. METHODS: Rat osteoblasts were isolated by two-part bony digestion/elements in culturing, and incubated in vitro at 37 degrees C, 5% carbon dioxide for 5 days until they multiplied and formed a monolayer on the bottom of dish. Twenty-eight rabbits were divided into 3 groups. Autograft of osteoblasts(group A), xenograft of osteoblasts(group B) and normal saline(group C) were implanted into the rectus abdominus muscle. The immunological and histological observations were performed after 1, 2, 4 and 8 weeks of transplantation. RESULTS: Cultured cells reached confluence within 5 days and was identified as osteoblasts by ALP staining and Bon kossa staining. The result of host versus graft reaction was negative. In group B, specific antibody reaction was detected 2 weeks and 4 weeks after transplantation. Cell mediated cytotoxicity was detected after 2 weeks, reached the peak value 4 weeks later, and then began to decline 8 weeks later. HE staining showed mass inflammatory cells and no ectopic ossification after 8 weeks. CONCLUSION: Heterogenic osteoblast transplantation will lead to an obvious change in host humoral and cellular immunity and lost the ability of bone formation. So, it can not be used for the reliable cell sources for osteocyte transplantation or tissue-engineering bone reconstruction.

Animals↗

PubMed2003

Effects of basic fibroblast growth factor on biological characteristics of osteoblasts.

OBJECTIVE: To elucidate the effects of exogenous basic fibroblast growth factor (bFGF) on biological characteristics of rat osteoblasts cultured in vitro. METHODS: The osteoblasts isolated from a Sprague-Dawley rat and cultured in vitro were treated with different concentrations of bFGF (5-50 ng/ml) respectively. At 24 hours after treatment, the proliferating cell nuclear antigen was measured with immunocytochemistry, alkaline phosphatase (ALP) activity was determined and the expression of transforming growth factor beta 1 (TGF-beta(1)) was detected to observe the effects of bFGF on growth and differentiation of osteoblasts. RESULTS: bFGF (5-50 ng/ml) could obviously promote the growth of osteoblasts. The intracellular expression of TGF-beta(1) mRNA increased significantly, but the intracellular ALP content decreased. CONCLUSIONS: bFGF can obviously stimulate the proliferation of osteoblasts and promote the synthesis of TGF-beta(1), but cannot promote the differentiation of osteoblasts.

Alkaline Phosphatase↗

PubMed2003

[Cloning of differentially displayed cDNAs involved in NaF-treated osteoblasts].

OBJECTIVE: To explore the effects of excessive fluoride on the gene expression of rat osteoblasts. METHODS: Rat osteoblasts were treated with 2.0 mmol/L of sodium fluoride (NaF) for two weeks in vitro, and difference in the gene expression between the NaF-treated and normal osteoblasts was compared with mRNA differential display (DD-PCR) technique. RESULTS: Among the six differentially expressed gene fragments which had been cloned, expression of the ribosomal protein L5 gene, ATPase Na(+)K(+) transporting beta polypeptide 3 gene, karyopherin alpha 2 gene and cis-Golgi body p28 gene was lower and expression of ubiquitous-conjugating enzyme E2D 3 gene and a newly-discovered gene fragment in this study showed up-regulated in the NaF-treated osteoblasts of the rats. CONCLUSIONS: Expression of genes changed in the osteoblasts after treatment with fluoride for two weeks and most of them associated with synthesis, transportation and processing of protein. It suggested that excessive fluoride could affect the protein synthesis in osteoblasts by changing the expression of the related genes. A novel gene related to excessive fluoride exposure was also found.

Animals↗

PubMed2004

[Culture of osteoblasts by serial explant culture and comparison of their characteristics].

OBJECTIVE: To Investigate a simple, economical and efficient method of primary osteoblast culture and compare their characteristics. METHODS: Primary osteoblasts of 1 st-4 th series explant culture from calvarial bones of neonatal Sprague-Dawley rats, were collected and osteoblasts shape, mitosis, proliferation, ALP activity and immunohistological expression of osteocalcin and BMP-2 observed. RESULTS: No difference was found in cell shape, spread, confluence, ALP activity as well as immunohistological stain of osteocalcin and BMP-2 of the osteoblasts, which had been harvested from the 1 st-4 th series explant cultures of Sprague-Dawley rats. CONCLUSION: Series explant culture can harvest the same kind of osteoblasts as the explant culture, and more osteoblasts can be obtained at a single time. It saves money and time and is easy to manipulate.

Alkaline Phosphatase↗

PubMed2004

Osteoblasts increase proliferation and release of pro-angiogenic interleukin 8 by native human acute myelogenous leukemia blasts.

BACKGROUND AND OBJECTIVES: Interactions between acute myelogenous leukemia (AML) blasts and non-leukemic cells in the bone marrow seem to be important for both disease development and susceptibility to chemotherapy. Recent studies have focused on the endothelial cells, but other non-leukemic cells may also be involved. In the present study we investigated how osteoblasts affect native human AML blasts. DESIGN AND METHODS: AML cells were derived from a large group of consecutive patients. The AML blasts and osteoblastic sarcoma cell lines (Cal72, SJSA-1) were incubated together in different chambers separated by a semipermeable membrane. We investigated effects of co-culture on proliferation, apoptosis and cytokine release. RESULTS: The cross-talk between these two cell populations, achieved via release of soluble mediators, resulted in increased AML blast proliferation, including increased proliferation of clonogenic progenitors, but did not affect spontaneous in vitro apoptosis. Both interleukin (IL) 1-b and granulocyte-macrophage colony-stimulating factor were involved in this growth-enhancing cross-talk, and normal osteoblasts could also increase the AML blast proliferation. Furthermore, co-culture of AML blasts with osteoblastic sarcoma cells as well as normal osteoblasts increased the levels of the pro-angiogenic mediator IL8. INTERPRETATION AND CONCLUSIONS: Our in vitro results suggest that the release of soluble mediators by osteoblasts supports leukemic hematopoiesis through two major mechanisms: (i) direct enhancement of AML blast proliferation; and (ii) enhanced angiogenesis caused by increased IL8 levels.

Apoptosis↗

PubMedDate not supplied

Ets2 transcription factor inhibits mineralization and affects target gene expression during osteoblast maturation.

Our goal is to understand how Ets family transcription factors affect the genetic programs that control bone development. Modest overexpression of Ets2 in transgenic mice leads to Down's syndrome-like bone abnormalities. We observed that in the MC3T3-E1 in vitro model of osteoblast development, mature osteoblasts have very high levels of Ets2 relative to the immature preosteoblasts. We hypothesized that overexpression of Ets2 could have noticeable effects on gene expression, and found that exogenous Ets2 expression results in a complete lack of mineralized matrix in stable Ets2 transfected cells. Our cDNA microarray-based expression profiling of preosteoblasts vs. differentiated osteoblasts revealed several genes previously unrecognized as having roles in osteoblast maturation and up-regulated only in the mature osteoblasts. The promoters of these genes and known osteoblast marker genes were examined for Ets transcription factor binding sites (EBSs). Interactions of these sites with Ets2 protein were tested by EMSA. In vitro expressed Ets2 protein was able to form a protein:DNA complex with both known (Bsp, Opn, ON) and novel (Btg2, CysC, Lum) bone-related genes. In addition, Cbfa1 was found to interact with Ets2, forming a complex on the Opn promoter.

Animals↗

PubMed2004

Role of albumin in osteoblastic cells: enhancement of cell proliferation and suppression of alkaline phosphatase activity.

The role of albumin in osteoblastic cells was investigated. Osteoblastic MC3T3-E1 cells with subconfluent monolayers were cultured for 24 to 72 h in a medium without fetal bovine serum (FBS) in the presence or absence of albumin (0.25, 0.5, or 1.0 mg/ml of medium). The number of osteoblastic cells was significantly increased by culture for 24 to 72 h in the presence of albumin (1.0 mg/ml). The effect of albumin in increasing cell number was completely abolished in the presence of PD98049 (10(-7) M), staurosporine (10(-7) M), or dibucaine (10(-7) M), which is an inhibitor of various protein kinases. Also, the stimulating effect of albumin on cell proliferation was completely prevented in the presence of cycloheximide (10(-7) M), an inhibitor of protein synthesis, or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), an inhibitor of transcriptional activity. DNA content was significantly increased in the cells cultured with albumin (1.0 mg/ml) addition for 24 to 72 h. Alkaline phosphatase activity in the cells, which participates in osteoblastic calcification, was significantly decreased by the culture with albumin (0.25, 0.5, or 1.0 mg/ml) for 24 to 72 h. The expression of insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 mRNAs using transcription-polymerase chain reaction (RT-PCR) analysis in osteoblastic cells was not significantly altered by culture for 48 h with albumin (1.0 mg/ml). This study demonstrated that albumin had a role in the regulation of osteoblastic cell function.

Albumins↗

PubMedDate not supplied

The effect of cyclooxygenase-2 (COX-2) inhibition on human prostate cancer induced osteoblastic and osteolytic lesions in bone.

BACKGROUND: The mechanism of bone formation by osteoblastic prostate cancer metastases is not well defined. Using knockout mice, it has been demonstrated that prostaglandins produced by COX-2 are critical for fracture repair. Therefore, our aim was to determine if COX-2 plays a role in the bone formation in osteoblastic prostate cancer metastases in bone. MATERIALS AND METHODS: We assessed the influence of pharmacologic COX-2 inhibition in a SCID mouse intratibial injection model of bone metastasis using two human prostate cancer cell lines that produce either osteoblastic lesions (LAPC-9) or osteolytic lesions (PC-3, negative control). SC-58236, a COX-2 specific inhibitor, was used at a dose of 3 mg/Kg intraperitoneally 3 times per week in the Treatment groups for 8 weeks until sacrifice. RESULTS: Western blot for COX-2 demonstrated that LAPC-9 cells expressed high levels of COX-2 while PC-3 cells did not. Treatment with SC-58236 significantly reduced the size of osteoblastic lesions after LAPC-9 injection based on both radiographic and histomorphometric criteria compared to the control group. In contrast, large osteolytic lesions were seen in both control and SC-58236 treated animals after PC-3 cell injections. The results of this study indicate that COX-2 inhibition can decrease the size of osteoblastic lesions produced by LAPC-9, a human prostate cancer cell line that expresses high levels of COX-2. This treatment had no effect on the osteolytic activity of PC-3 cells. CONCLUSION: These findings suggest that the progression of osteoblastic metastases induced by human prostate cancer cells may be limited by COX-2 inhibitors.

Animals↗

PubMed2005

[The effects of 1alpha,25-dihydroxyvitamin D3 in regulation matrix metalloproteinase and tissue metalloproteinase inhibitors in human osteoblasts].

OBJECTIVE: To characterize the effects of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] on the expression of matrix metalloproteinase (MMP)-1, MMP-2, membrane-type MMP-1 (MT1-MMP), tissue inhibitors of metalloproteinase-1 (TIMP-1) in human osteoblast, and understand the mechanism by which 1alpha,25(OH)2D3 exert on bone. METHODS: Osteoblasts were interfered by 1alpha,25(OH2D3. Western blot were used to show the action of 1alpha,25(OH)2D3 on the expression of MT1-MMP protein in human osteoblasts. ELISA was done to examine the effect of 1alpha,25(OH)2D3 on the activity of MMP-2. Northern blot analysis was performed to detect vitamin D receptor mRNA levels and to evaluate the effect of 1alpha,25(OH)2D3 on MT1-MMP mRNA levels. RESULTS: The results showed that 1alpha,25(OH)2D3 had no effect on the expression of MMP-1, MMP-2 and TIMP-1 in human osteoblasts; 10(-10) - 10(-8) mol/L 1alpha,25(OH)2D3 induced MT1-MMP expression in a dose-dependent manner (P < 0.05), 10(-10) - 10(-8) mol/L 1alpha,25(OH)2D3 induced the activation of proMMP-2 in a dose-dependent manner in human osteoblasts[The activity of MMP-2 was (42.3 +/- 8.6), (64.4 +/- 11.4), (93.5 +/- 9.9) microg/L respectively, P < 0.05]. CONCLUSION: 1alpha,25(OH)2D3 may stimulate bone resorption by inducing MT1-MMP production in osteoblasts.

Adult↗

PubMed2005

[Biological effects of nano-hydroxyapatite/polyamide 66 on the osteoblast].

OBJECTIVE: To evaluate the biological effects of nano-hydroxyapatite/polyamide 66(nHA-PA66) on the growth and activity of osteoblast. METHODS: MTT assay was used to determine the growth of osteoblast, enzymatic measure was used to determine the activity of ALP and quantitative RT-PCR (QRT-PCR) to evaluate the changes of osteoclacin mRNA expression in osteoblasts treated by DMEM eluate of nHA-PA66. RESULTS: Osteoblasts of different test groups demonstrated relative proliferation rate ranging from 98% - 106% without dose-dependent effect. The ALP activity and osteocalcin mRNA expression were similar in test and control groups (P > 0.05). CONCLUSION: nHA-PA66 has no negative effects on the osteoblast and its osteoblast-compatibility is proved.

Durapatite↗

PubMedDate not supplied

Effects of glycosaminoglycans on cell proliferation of normal osteoblasts and human osteosarcoma cells depend on their type and fine chemical compositions.

Osteoblastic cells produce a complex extracellular matrix (ECM) composed of a mixture of proteoglycans (PGs), collagens and non-collagenous proteins. The interaction of proteoglycans with matrix effector macromolecules via either their glycosaminoglycan (GAG) chains or their protein core is critical in regulating a variety of cellular events. Alterations in the structural composition of the GAG/PG component of the ECM may have important consequences on cell proliferation and/or differentiation. Human osteoblasts and two osteosarcoma cell lines, able to produce galactosaminoglycan (GalAGs) and heparan sulphate (HS)-containing proteoglycans, were treated with their main GAG chain types, and the effects on cell growth were examined. Chondroitin sulphate (CSA) and dermatan sulphate (DS) inhibited cell proliferation of all osteoblastic cell lines at high concentration (100 microg/ml). DS showed the stronger inhibitory effect, probably due to the presence of flexible IdoA residues that provide a greater variety in conformation to these macromolecules. Heparin strongly inhibited the proliferation rates of both normal osteoblasts and transformed osteoblastic cells at concentrations > or = 1 microg/ml. The presence of large amounts of IdoA-derived trisulphated disaccharides, responsible for the overall negative charge of heparin, should be considered as a critical factor for the inhibition of cell proliferation. The obtained results suggest that matrix GAGs are factors which affect cell growth of both malignant and normal cells of the osteoblastic lineage in a concentration-dependent manner. This effect is closely related to the fine chemical structure of GAGs, i.e. the presence of L-iduronic acid and the degree of sulphation.

Bone Neoplasms↗