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PubMed2003

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival.

Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone-derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.

Apoptosis↗
PubMed1987

Estradiol-17 beta-induced morphometric changes in chick embryo femurs.

The influence of exogenous estradiol-17 beta (E2) on chick embryo femur morphology was assessed. Fertile chicken eggs were air cell injected with 18.75, 37.5, or 75 micrograms E2/.1 ml distilled water: ethanol (7:3, v/v) on Days 10, 12, and 14 of incubation. Controls received vehicle only (.1 ml) on the same days. On Day 16 of incubation, right femurs were excised, and midshaft cross sections were examined by light microscopy. Structural differences were quantified using a computerized histomorphometric technique. Injection of E2 produced significant (P less than .01) dose-dependent elevations in mean femur total osseous tissue area, bone matrix area, percent of matrix surfaces covered by osteoblasts, and percent of matrix area occupied by osteocytes when compared with controls. Estradiol was ineffective in inducing medullary bone formation in chick embryo femurs. We conclude that E2 is involved in bone matrix formation processes in chick embryos. The lack of medullary bone formation upon E2 treatment in chick embryos is perhaps an indication that, as in growing (immature) birds, it is likely that endogenous testosterone levels in Day 16 chick embryos are insufficient to support medullary bone growth.

Animals↗
PubMedDate not supplied

On the origin of cells in heterotopic bone formation.

Previous experiments have demonstrated that decalcified, lyophilized bone matrix is a powerful substratum for differentiation of mesenchymal cells into new bone. The present experiment employs parabiosis as a tool to distinguish between cells of hemotogenous origin and mesenchymal cell populations derived from the site of implantation of bone matrix. The results indicate that the osteoinductor releasing cells are blood-borne monocytoid cells which enter the tissues by diapedesis and become histiocytes, macrophages, matrixclasts and osteoclasts; their precursors are derived from bone marrow at sites remote from the area of bone induction. The cell populations responding to the osteoinductor released by this mechanism develop into osteoblasts and osteocytes and are the progeny of perivascular mesenchymal cells.

Animals↗
PubMed1997

Osteogenic response to hydroxyapatite-fibrin implants in maxillofacial bone defects.

Bone formation in hydroxyapatite-fibrin implants has been reported several times. However, available studies refer to experimental animals, or are limited to short periods after implantation. We report the results of histological, histochemical and ultrastructural studies carried out 2.5-8 yr after implantation of non-resorbable, porous hydroxyapatite (HA) and fibrin glue in human maxillofacial bones. Prominent ossification was found in all cases, with the presence of normally structured spongy bone. HA granules were embedded in the calcified bone matrix. They had not elicited inflammatory reactions and did not induce bone resorption. Ossification was preceded by the appearance of alkaline phosphatase activity on fibroblast-like cells, and by the formation of dense collagenous layers, similar to osteoid borders, on the surface of HA granules. The early phases of the calcification process occurred in these borders, with the appearance of calcification nodules adjacent to alkaline phosphatase-positive osteoblast-like cells. A remodeling process similar to that occurring in normal bones was found in the newly formed bone. These results justify the conclusion that HA-fibrin implants lead to the formation of long-lasting bone that does not differ from that of the normal maxillofacial skeleton. Mixing the HA granules with fibrin has the advantage of creating an easily mouldable material which can be adapted to any skeletal surface and stays in place after surgery.

Alkaline Phosphatase↗
PubMed1984

Resorption of implanted bone prepared from normal and warfarin-treated rats.

Bone that was virtually depleted of the vitamin K-dependent protein, osteocalcin, and 93% reduced in the concentration of its characteristic amino acid, gamma-carboxyglutamic acid, was obtained from rats treated with warfarin for 6 wk. Osteocalcin-deficient bone particles were resistant to resorption when implanted subcutaneously in normal rats. The relative resorption was 60% of control bone, as measured by histomorphometry as percent of bone particles in the field. Additionally, the number of multinucleated cells around the bone particles was reduced by 54%. These data suggest that osteocalcin is an essential component for bone matrix to elicit progenitor-cell recruitment and differentiation necessary for bone resorption.

Animals↗
PubMed1995

Lumbar intertransverse-process spinal arthrodesis with use of a bovine bone-derived osteoinductive protein. A preliminary report.

The use of a bovine bone-derived osteoinductive protein extract as a bone-graft substitute was evaluated in a rabbit model of intertransverse process arthrodesis of the lumbar spine. Forty-five adult New Zealand White rabbits had arthrodesis between the fifth and sixth lumbar vertebrae with use of one of three graft materials: autogenous iliac-crest bone, osteoinductive protein delivered in an allogeneic demineralized bone matrix/collagen carrier, or demineralized bone matrix/collagen carrier or demineralized bone matrix/collagen carrier without osteoinductive protein. Fusion was assessed by manual palpation, radiography, biomechanical testing, and light microscopy at two and five weeks after the operation. At two weeks, light microscopic analysis of the arthrodesis site in which osteoinductive protein had been used showed that most of the demineralized bone matrix was still present, with small amounts of membranous and endochondral bone formation at the peripheral margins of the implant. Light microscopic analysis of the five-week specimens showed increased new-bone formation and a more homogeneous and mature fusion mass with the osteoinductive bone protein than with the autogenous bone graft. At five weeks, the fusions with the osteoinductive protein extract were characterized by more secondary spongiosa, with formation of bone marrow centrally and a cortical rim peripherally. Of the thirty-five rabbits that were examined at five weeks, all ten in the group that had received osteoinductive bone protein had a solid fusion, but the rate of fusion was significantly less in the other two groups: eight of thirteen rabbits (p = 0.05) in the group that had received autogenous bone graft and two of twelve rabbits (p = 0.0001) in the group that had received demineralized bone matrix/collagen carrier without osteoinductive bone protein. The use of osteoinductive bone protein resulted in stronger (p = 0.02) and stiffer (p = 0.005) fusions compared with those obtained with the use of autogenous iliac-crest graft.

Animals↗
PubMed1999

Impaction bone-grafting increases the holding power of cancellous screws in the femoral head. A pull-out study in human cadaver hips.

We studied the effect of impaction of fresh cancellous bone or demineralized bone matrix (DBM) around cancellous screws in 25 cadaver femoral heads. The bone mineral content (BMC) of femoral heads was measured to determine if greater relative increase in holding power will be achieved by impaction-grafting, as the BMC of the specimen decreases. A 60% (p < 0.001) relative increase in the pull-out force was achieved by impaction-grafting with DBM, compared to non-grafted controls. The augmenting effect of fresh cancellous bone graft and DBM did not differ significantly. The relative improvement in holding power was not inversely correlated to femoral head BMC, but was inversely related to the pull-out resistance of non-grafted control screws. These findings suggest that impaction-grafting provides significantly better hold of cancellous screws in femoral heads.

Bone Density↗
PubMed1990

[Methods of using component alloplasty in osteo-articular surgery].

In accordance with the principle of component plasty the authors have developed methods of procurement of the alloplastic material and its use. The following plastic materials are procured and supplied to health service: spongy bone allotransplants devoid of bone marrow (allospongiosis BS), allotransplants of the viable joint cartilage on a thin bone base (allocartilage BS) and demineralized bone matrix in the form of a film for protection of the bone formation zone and stimulation of osteogenesis (allofilm BS). Results of the component plasty in 300 patients are much superior in their efficiency to those known earlier. The terms of restorative processes became 2-3 times shorter. The above plastic materials are recommended for wide use in osteo-articular surgery.

Adult↗
PubMed1997

Interleukin-6 and its soluble receptor cause a marked induction of collagenase 3 expression in rat osteoblast cultures.

Interleukin-6 (IL-6), a cytokine produced by skeletal cells, increases bone resorption, but its effects on collagenase expression are unknown. We tested the effects of IL-6 and its soluble receptor on collagenase 3 expression in osteoblast-enriched cells from fetal rat calvariae (Ob cells). IL-6 caused a small increase in collagenase mRNA levels, but in the presence of IL-6-soluble receptor (IL-6sR), IL-6 caused a marked increase in collagenase transcripts after 2-24 h. In addition, IL-6sR increased collagenase mRNA when tested alone. IL-6 and IL-6sR increased immunoreactive collagenase levels. Cycloheximide and indomethacin did not prevent the effect of IL-6 and IL-6sR on collagenase mRNA levels. IL-6 and IL-6sR did not alter the decay of collagenase mRNA in transcriptionally arrested Ob cells and increased the levels of collagenase heterogeneous nuclear RNA and the rate of collagenase gene transcription in Ob cells. IL-6 and IL-6sR increased collagenase 3 mRNA in MC3T3 cells but only modestly in skin fibroblasts. IL-6 and IL-6sR enhanced the expression of tissue inhibitor of metalloproteinases 1. In conclusion, IL-6, in the presence of IL-6sR, increases collagenase 3 synthesis in osteoblasts by transcriptional mechanisms. This effect may contribute to the action of IL-6 on bone matrix degradation and bone resorption.

Animals↗
PubMed1993

Osteogenic activity of bone morphogenetic protein and hydroxyapatite composite implants.

In an experimental study in rats hydroxyapatite (HA) ceramics of characteristics and inactive rat bone matrix were investigated comparatively for their suitability as carriers for osteoinductive factors. Bone morphogenetic protein was extracted from long bones of pigs under dissociative conditions and partially purified by gel filtration. The resulting pBMP was combined with the granular hydroxyapatite ceramics Osprovit, Algipore, Frialit and inactive rat bone matrix (IBM) by precipitation of aliquots of this pBMP fraction onto pellets of each carrier material. The osteogenic activity of these composite implants and of corresponding controls was bioassayed by implantation into muscle pouches of immunodeficient rats. All pBMP-HA ceramic implants elicited ectopic bone formation within 25 days after implantation, whereas control implants did not show any osteoinductive ability. Alkaline phosphatase (AP) activity of the explant tissues was determined for quantitation of bone formation. Due to the high incidence of bone formation found in each pBMP group all HA ceramics tested seem to be basically suitable as carriers for osteoinductive factors. Algipore, a highly porous phycogen HA ceramic, was found to be quantitatively superior to all other materials investigated due to its very large surface available for protein binding.

Animals↗
PubMed2001

[Experimental study in rabbit on repair of radial bone defect by bioactive degradable polymer].

OBJECTIVE: To investigate the availability of bone defect repair by degradable porous polycaprolactam (PCL) as the carrier of bone morphogenetic protein (BMP). METHODS: Three different kinds of bone substitutes, including decalcified bone matrix, PCL-BMP compounds and simple PCL, were implanted into the radial bone defects in 36 rabbits, and in the other 12 rabbits the bone defects were left untreated as control. X-ray examination, X-ray morphometry, histological and electron microscopic observation were performed at different time after operation. RESULTS: The quantity of new bone formation in PCL-BMP group was prior to that in simple PCL group. The pattern and speed of bone defect repair in PCL-BMP group were similar to those in decalcified bone matrix. Electron microscopic observation showed that the PCL-BMP group degraded faster than simple PCL group, which was more suitable for bone repair. CONCLUSION: PCL is a good carrier of BMP with potential for clinical use.

Animals↗
PubMed1994

Calcitonin inhibits osteopontin mRNA expression in isolated rabbit osteoclasts.

Recent evidence indicates that osteopontin (Opn), one of the bone matrix proteins, plays an important role in the attachment of osteoclasts to bone matrix. Besides being elaborated by osteoblasts, this protein is also produced by osteoclasts. The present study was performed to examine the effect of calcitonin (CT) on Opn mRNA expression of isolated rabbit osteoclasts and to clarify the second messenger signaling of this effect. Eel CT inhibited Opn mRNA expression as well as bone-resorbing activity of isolated rabbit osteoclasts. Eel CT caused a transient increase in intracellular calcium followed by a sustained increase as well as an increase in cAMP production in these cells. Dibutyryl-cAMP (10(-4) M) and Sp-cAMPS (10(-4) M), an activator of cAMP-dependent protein kinase (PKA), as well as A23187 (10(-7) M), a calcium ionophore, and phorbol myristate acetate (10(-7) M), an activator of protein kinase C (PKC), caused a significant inhibition of Opn mRNA expression, and suppressed bone-resorbing activity of isolated osteoclasts. The present study is the first to demonstrate that CT inhibits Opn mRNA expression in isolated rabbit osteoclasts, presumably through the activation of PKA and calcium/PKC pathways, by which the bone-resorbing activity might be attenuated subsequently.

Animals↗
PubMed2004

Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Calcific aortic stenosis, the major heart valve disease encountered in the elderly, leads to massive calcium deposition in the valve leaflets that morphologically resembles bone formation. Recent studies have demonstrated the expression of various bone-associated proteins in stenotic valves, suggesting that valvular calcification may be an actively regulated process. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, and bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor cytokine superfamily, are known to participate in the regulation of bone development and maturation. Their pathogenetic role in calcific aortic stenosis is unknown. METHODS: Using an immunoperoxidase technique and antibodies against BSP and BMP-2, the expression of BSP and BMP-2 was examined in 16 human aortic valves with calcific aortic stenosis obtained at valve replacement, and in seven normal autopsy controls without signs of aortic stenosis. RESULTS: By semiquantitative scoring, stenotic valves showed a significantly increased staining of BSP in cells and extracellular matrix as compared to control valves (2.7 +/- 0.1 versus 0.6 +/- 0.2 score units, p <0.001). Marked BMP-2 expression was detected in stenotic valves, mostly in cell-rich areas associated with focal calcium deposits, but no specific staining for BMP-2 was detected in control valves (1.5 +/- 0.2 versus 0.0 +/- 0.0 score units, p <0.001). CONCLUSION: These results demonstrate for the first time that BSP and BMP-2 are differentially expressed in normal aortic valves and in aortic stenosis, thereby supporting the concept that valvular calcification might be based on an actively regulated process involving BSP and BMP-2.

Aged↗
PubMed1993

Effect of a persistent inflammatory process on experimental heterotopic ossification. The influence of macrophages.

1. We investigated the effect of a persistent carrageenin- or nystatin-induced inflammatory reaction on heterotopic ossification produced by the subcutaneous implant of a demineralized bone matrix in female Swiss mice (25 to 35 g). 2. Subcutaneous carrageenin injection (0.3 ml of a 2% solution in saline) into mice induced an inflammatory reaction characterized by a mature granuloma predominantly of macrophages containing particles of the irritant in their cytoplasm and which remained unchanged until the end of the experiment (40th day). 3. Subcutaneous nystatin inoculation (30,000 IU in 0.3 ml saline) induced an inflammatory reaction consisting initially of macrophages (4th day) but later turning into an epithelioid granuloma (7th day) consisting predominantly of epithelioid cells and which was present up to the 21st day when it was gradually replaced by adipocytes up to the 30th day. 4. An intramuscular implant of demineralized bone matrix (DBM, approximately 10 mg) induced the formation of cartilage and bone tissue and of hemopoietic bone marrow (heterotopic ossification) in 100% of the control animals (N = 5). An intramuscular DBM implant in animals that received carrageenin (N = 19) or nystatin (N = 21) induced heterotopic ossification in 100 and 57% (P < 0.01) of the animals, respectively. 5. The response to a dorsal subcutaneous DBM implant was essentially negative in control animals (N = 5), whereas implants performed near the site injected with carrageenin (N = 28) or nystatin (N = 31) produced a response in 71 (P < 0.01) and 36% (P < 0.01) of the animals, respectively. A DBM implant into the contralateral (control) dorsal subcutaneous tissue of the same animals that received carrageenin (N = 25) or nystatin (N = 29) resulted in heterotopic ossification in 64 (P < 0.01) and 7% of the animals, respectively. 6. The results suggest that the macrophages present in the mature granuloma induced by carrageenin somehow favored the development of metaplastic plates after subcutaneous DBM implant and that this effect may be systemic since the same response was observed in contralateral subcutaneous tissue.

Animals↗
PubMed1992

Growth and morphogenetic factors in bone induction: role of osteogenin and related bone morphogenetic proteins in craniofacial and periodontal bone repair.

Bone has considerable potential for repair as illustrated by the phenomenon of fracture healing. Repair and regeneration of bone recapitulate the sequential stages of development. It is well known that demineralized bone matrix has the potential to induce new bone formation locally at a heterotopic site of implantation. The sequential development of bone is reminiscent of endochondral bone differentiation during bone development. The collagenous matrix-induced bone formation is a prototype model for matrix-cell interactions in vivo. The developmental cascade includes migration of progenitor cells by chemotaxis, attachment of cells through fibronectin, proliferation of mesenchymal cells, and differentiation of bone. The bone inductive protein, osteogenin, was isolated by heparin affinity chromatography. Osteogenin initiates new bone formation and is promoted by other growth factors. Recently, the genes for osteogenin and related bone morphogenetic proteins were cloned and expressed. Recombinant osteogenin is osteogenic in vivo. The future prospects for bone induction are bright, and this is an exciting frontier with applications in oral and orthopaedic surgery.

Alveolar Process↗
PubMed2004

Analysis of human bone sialoprotein in normal and pathological tissues using a monoclonal antibody (BSP 1.2 mab).

Bone sialoprotein (BSP), a phosphorylated and sulphated glycoprotein that is expressed by mineralized connective tissues is also produced in tumors that metastasize to bone. To facilitate studies of BSP expression in normal and pathological human tissues a monoclonal antibody (BSP 1.2 mab) was raised against human bone BSP. BSP 1.2 mab was shown by ELISA assays to recognize the epitope "DEYSY" (amino acids 279-283) that is conserved in mammalian BSP sequences. However, whereas the antibody recognized recombinant BSPs expressed in bacteria, it did not recognize native forms of rat or pig BSP in which the first tyrosine of the DEYSY peptide sequence appears to be modified. Immunostaining of embryonic human tibiae and calvariae with BSP 1.2 mab showed strong reaction in osteoblasts and osteocytes with relatively weak staining of the bone matrix, suggesting that the BSP 1.2 mab epitope is partially masked in the bone matrix. BSP 1.2 mab also stained osteosarcoma cells and normal trophoblastic cells in the placenta in areas of microcrystalline deposits. Cancer cells in primary breast tumors, lymph nodes, and secondary bone metastases from individual patients were stained strongly by BSP 1.2 mab. Although BSP 1.2 mab also stained breast cancer carcinoma cell lines and SaOS2 osteosarcoma cells, biosynthesis of radiolabelled BSP could not be demonstrated in breast cancer cells. Notably, the staining of BSP in the breast cancer cells was diffuse contrasting the punctate staining, typical of secreted proteins, in SaOS2 cells. These studies, therefore, have identified a unique epitope in human BSP recognized by a monoclonal antibody, BSP 1.2 mab, which can be used for the unequivocal identification of BSP in normal and pathological human tissues.

Antibodies, Monoclonal↗
PubMed2004

The metalloproteinase MT1-MMP is required for normal development and maintenance of osteocyte processes in bone.

The osteocyte is the terminally differentiated state of the osteogenic mesenchymal progenitor immobilized in the bone matrix. Despite their numerical prominence, little is known about osteocytes and their formation. Osteocytes are physically separated in the bone matrix but seemingly compensate for their seclusion from other cells by maintaining an elaborate network of cell processes through which they interact with other osteocytes and bone-lining cells at the periosteal and endosteal surfaces of the bone. This highly organized architecture suggests that osteocytes make an active contribution to the structure and maintenance of their environment rather than passively submitting to random embedding during bone growth or repair. The most abundant matrix protein in the osteocyte environment is type-I collagen and we demonstrate here that, in the mouse, osteocyte phenotype and the formation of osteocyte processes is highly dependent on continuous cleavage of type-I collagen. This collagenolytic activity and formation of osteocyte processes is dependent on matrix metalloproteinase activity. Specifically, a deficiency of membrane type-1 matrix metalloproteinase leads to disruption of collagen cleavage in osteocytes and ultimately to the loss of formation of osteocyte processes. Osteocytogenesis is thus an active invasive process requiring cleavage of collagen for maintenance of the osteocyte phenotype.

Animals↗
PubMed2000

A new approach to demonstrate cellular activity in bone formation adjacent to implants.

Bone tissue repeatedly formed in titanium 6-aluminum 4-vanadium rabbit bone harvest implants was collected in vivo at various times between 12 days and 5 weeks. Qualitative and quantitative examinations on undecalcified thin sections were performed in the light microscope. The amount of bone tissue was calculated on routinely stained sections. Alkaline (ALP) and acid phosphatase (ACP) enzyme activities were investigated. We also performed immunohistological detection of bone matrix proteins. Increasing bone density as well as an increasing mineralization of the tissue was observed in the biopsies with increasing time. The ALP and ACP activities were similar at short times (12 days and 2 weeks). With increasing time the ALP activity was stronger than that of ACP. The results from the immunohistochemical detection of osteonectin, osteopontin, bone sialoprotein, and collagen I and II demonstrated changes in the tissue differentiation with time. The tissue formation in the canal became more mature with time of ingrowth, as observed with the various techniques used in this study. Owing to these methodical developments, undecalcified ground sections may be used for detailed analysis of various phases of tissue formation in close proximity to implants.

Acid Phosphatase↗