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PubMed2001

Physiopathological basis of bone turnover.

Bone remodeling involves the continuous removal of bone (bone resorption) followed by synthesis of new bone matrix and subsequent mineralization (bone formation). The principal cells that mediate the boneforming processes of the skeleton are osteoblast cells. They are responsible for the production of the matrix constituents and the differentiation of osteoblasts from stromal cell precursors is stimulated by several hormonal and non-hormonal molecules. On the other hand, the osteoclasts are giant multinucleated cells responsible of bone resorption. They are formed in the bone marrow and mature cells are stimulated by PTH and locally acting agents such as transforming growth factor alpha (TGFalpha), tumor necrosis factor (TNF) interleukin 1 (IL-1) and interleukin 6 (IL-6). The first events during bone remodeling is osteoclast activation, followed by osteoclast formation, polarization constitution of the ruffled border, resorption and ultimately apoptosis. Osteoclast apoptosis is followed by a series of sequential changes in cells in the osteoblast lineage, including osteoblast chemotaxis, proliferation and differentiation, which in turn is followed by formation of mineralized bone and cessation of osteoblast activity. The final phase of the formation process is cessation of osteoblast activity. The resorption lacunae are usually repaired either completely or almost completely. Understanding the sequence of cellular events may be important to better know the mechanisms responsible for bone loss that occurs in age and in several pathological conditions.

Bone Remodeling↗

PubMed2005

Downregulation of Wnt signaling by increased expression of Dickkopf-1 and -2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells.

UNLABELLED: We examined the role of Wnt/beta-catenin signaling in successive stages of osteoblast differentiation. It has been shown that Wnt signaling in mature osteoblasts needs to be downregulated to enable the formation of a mineralized matrix. Using RNA interference, we showed that this is, at least in part, accomplished by upregulation of the Wnt antagonists Dickkopf-1 and -2. INTRODUCTION: The role of Wnt signaling in the initiation of osteoblast differentiation has been well studied. However, the role during late-stage differentiation is less clear. We have examined the role of Wnt/beta-catenin signaling in successive stages of osteoblast differentiation. MATERIALS AND METHODS: We treated murine bone marrow and mesenchymal stem cell-like KS483 cells with either LiCl or Wnt3A during several stages of osteoblast differentiation. In addition, we generated stable KS483 cell lines silencing either the Wnt antagonist Dkk-1 or -2 RESULTS: Activation of Wnt signaling by LiCl inhibits the formation of a mineralized bone matrix in both cell types. Whereas undifferentiated KS483 cells respond to Wnt3A by inducing nuclear beta-catenin translocation, differentiated cells do not. This is at least in part accomplished by upregulated expression of Dkk-1 and -2 during osteoblast differentiation. Using RNA interference, we showed that Dkk-1 plays a crucial role in blunting the BMP-induced alkaline phosphatase (ALP) response and in the transition of an ALP+ osteoblast in a mineralizing cell. In contrast, Dkk-2 plays a role in osteoblast proliferation and the initiation of osteoblast differentiation. CONCLUSIONS: Our data suggest that Wnt signaling in maturing osteoblasts needs to be downregulated to enable the formation of a mineralized bone matrix. Furthermore, they suggest that Dkk-1 and Dkk-2 may have distinct functions in osteoblast differentiation.

Active Transport, Cell Nucleus↗

PubMed2000

Quantitative genetic analysis of circulating levels of biochemical markers of bone formation.

Carboxyterminal propeptide of type 1 collagen (PICP) and bone Gla-protein-osteocalcin (BGP) are the most important components of the organic bone matrix and play a key role in bone formation. To investigate whether and to what extent variation of the plasma levels of these indices of bone turnover depends on genetic factors, we studied 355 adults belonging to nuclear pedigrees. Genetic analysis was carried out in 2 steps: 1) variance decomposition analysis was performed using the FISHER statistical package; and 2) complex segregation analysis implemented in the program package MAN. The effect of age and gender differences, gender hormones, as well as PTH and vitamin-D (calcidiol) plasma levels were evaluated simultaneously with the parameters of variance analysis. The results showed that about 50% of PICP variation is attributable to genetic factors. The effect of age was significant among men and postmenopausal women, whereas calcidiol influenced variation of PICP in premenopausal women. The results of variance analysis showed that some 40% of BGP, adjusted for confounding variables, can be explained in genetic factors. Age and PTH were important covariates for osteocalcin in men and premenopausal women. Exploration of the maximum likelihood estimates of the various hypotheses concerning the mode of intergenerational transmission of PICP and BGP demonstrated a good correspondence to the Mendelian mode of inheritance (i.e., major gene effect).

Adolescent↗

PubMed2004

Endocytic trafficking in actively resorbing osteoclasts.

Endocytosis and the subsequent intracellular trafficking of the endocytosed material are important determinants of cellular function. Osteoclasts, cells of the monocyte/macrophage family, are specialized for the internalization and processing of bone matrix. Transcytosis of endocytosed material has been observed in osteoclasts but the precise mechanism controlling this process is unclear. Here, we investigate the regulation of these trafficking events. To establish the directionality and kinetics of trafficking events in resorbing osteoclasts, we devised a system using fluorescent low-molecular-weight markers as probes to follow the route taken by the digested bone matrix. We demonstrate that this route is largely distinct from the pathway followed by proteins taken up by receptor-mediated endocytosis at the basolateral plasma membrane. Endocytosis and transcytosis from the ruffled border are fast processes, with a half-life of the endocytosed material inside the cells of 22 minutes. We demonstrate the crucial role of the microtubule network in transport from the ruffled-border area and provide evidence for a role of the cytoskeleton in the overall efficacy of trafficking. Moreover, we analyse the effect of the V-ATPase inhibitor bafilomycin A1 on endocytic uptake, which gives insight into the pH-dependent regulation of membrane trafficking and resorption in osteoclasts.

Adenosine Triphosphatases↗

PubMed2004

Substance P enhances the inhibition of osteoblastic cell differentiation induced by lipopolysaccharide from Porphyromonas gingivalis.

BACKGROUND: Substance P (SP) is a multifunctional neuropeptide that transmits pain signals, regulates the immune system, and may modulate emotional stress. SP stimulates bone resorption activity of osteoclasts, and SP level in gingival crevicular fluid is correlated with the degree of periodontal inflammation. However, the exact roles of SP in bone metabolism and periodontal diseases are poorly understood. To elucidate the effect of stress on bone metabolism, we investigated the effect of SP on osteoblastic cell differentiation in the presence of lipopolysaccharide from Porphyromonas gingivalis (P-LPS). METHODS: The primary osteoblastic cells were isolated from fetal rat calvaria (RC) and cultured with SP, P-LPS, and an SP antagonist (SPa). The effects of SP on bone nodule (BN), alkaline phosphatase (ALPase) activity, mRNA expressions of SP receptor, bone matrix proteins, and Cbfa 1 were investigated. RESULTS: SP stimulated the expression of SP receptor mRNA in RC cells and enhanced its expression in the presence of P-LPS (50 ng/ml). SP inhibited BN formation and ALPase activity in a dose-dependent manner (10(-7) to 10(-5) M) and further suppressed mRNA expression of bone sialoprotein, osteopontin, and osteocalcin but not of type I collagen mRNA. The inhibitory effects were enhanced in the presence of P-LPS and blocked by Spantide III. Furthermore, the expression of Cbfa 1 mRNA was also markedly suppressed in the presence of SP and P-LPS. CONCLUSION: These findings suggest that SP inhibits osteoblastic cell differentiation and may be related to bone metabolism in periodontal diseases under conditions of stress.

Alkaline Phosphatase↗

PubMed1994

Mechanisms of hypocalcemia and markers of bone turnover in alcohol-intoxicated drinkers.

Studies of hypocalcemia and osteoporosis frequently encountered in heavy users of alcohol have previously been performed on alcoholic people who have already recovered from alcohol intoxication. Bone and mineral metabolism during and after the intoxication may be different. We measured serum parameters of bone and mineral metabolism in 26 alcohol-intoxicated men and in 19 healthy control men. Although serum ionized calcium was 12% (P < 0.0001) lower in the patients than in the controls, serum intact parathyroid hormone was similar in the study groups. As reflected by decreased serum levels of osteocalcin (-43%; P < 0.001), bone formation was depressed in the patients. Serum cross-linked carboxyterminal telopeptide of human type I collagen (ICTP), a novel parameter of bone matrix degradation, was 9% higher in the patients (P = 0.03) than controls. The positive correlation between serum osteocalcin and ICTP in the controls (r = 0.59, P < 0.01) was absent in the patients (r = 0.05, P = 0.8). We conclude that in alcohol-intoxicated alcohol users, the parathyroid glands do not respond normally to a hypocalcemic stimulus, and that depressed bone formation is uncoupled from accelerated bone resorption.

Adult↗

PubMed2004

Histomorphometric evaluation of bone regeneration using allogeneic and alloplastic bone substitutes.

PURPOSE: The purpose of this investigation was to assess bone regeneration in critical sized defects in the rabbit calvarium using allogeneic and alloplastic bone substitutes. MATERIALS AND METHODS: Thirty New Zealand White rabbits were divided into 3 groups of 10 animals each. Bilateral 15 mm x 17 mm calvarial defects were made in the parietal bones of each animal. Group 1 had demineralized bone matrix (DBM) gel placed in one defect, while the other defect was left unfilled and served as the control. Group 2 had one defect filled with calcium hydroxide (CaOH)-treated DBM gel and the other defect filled with DBM gel. Group 3, the calcium-phosphate cement group, had Norian CRS (Norian Corp, Cupertino, CA) placed on one side and Bone Source (Howmedica Leibinger, Dallas, TX) placed on the contralateral side. Five animals in each group were killed at 6 and 12 weeks. Data analysis included qualitative assessment of the calvarial specimens and radiographic evaluation. Histomorphometric analysis was used to quantify the amount of new bone within the defects. RESULTS: Histomorphometric analysis showed that DBM gel-treated defects had significantly more new bone at 12 weeks compared with all other groups. There was no significant difference between defects filled with CaOH-treated DBM gel and those filled with DBM gel at 12 weeks. In group 3, Norian CRS- and Bone Source-treated defects were not statistically different from the unfilled controls. CONCLUSION: DBM gel was an effective allogeneic bone substitute that showed reliable osseous healing of critical size defects in the rabbit calvarium. The addition of CaOH to DBM gel did not significantly improve the bone regenerative capacity of the DBM gel. Both Norian CRS and Bone Source did not promote bone regeneration in this animal model.

Animals↗

PubMedDate not supplied

Ultrastructural abnormalities in bone and calcifying cartilage in two siblings with a newly described recessive lethal chondrodysplasia.

Ultrastructural abnormalities in bone and calcifying cartilage are presented for a recently identified lethal chondrodysplasia. Two siblings, aged 20 and 30 weeks of gestation, showed severe short-limb dwarfism and histologically distinct, highly disorganized masses of cartilage, bone, and mesenchymal tissue in the long bones. Regions of inappropriate cartilage calcification showed unusual, electron-dense, amorphous islands of mineralization and larger, less dense, layered calcified masses that occasionally entrapped chondrocytes. Bone abnormalities included abnormal cartilage-bone transition at the growth plate, general bone matrix disorganization due to irregularly oriented bundles of collagen, mineral crystals on the osteocyte lacunar rim, and accumulations of thickened collagen fibrils, also along the osteocyte lacunar rim. These findings point to abnormal calcification and mineralization distinct from those seen in other reported skeletal dysplasias. These abnormalities are associated with an anarchic distribution of mesenchymelike tissue infiltrating the cartilage and bone.

Bone Matrix↗

PubMed1991

Bone induction in nonhuman primates. An experimental study on the baboon.

Development leading to local bone differentiation in response to intramuscular and subcutaneous implantation of demineralized bone matrix has been predominantly investigated in rodents. To investigate bone differentiation by induction in primates, diaphyseal bone was harvested from ten male baboons and chemosterilized to obtain autolyzed, antigen-extracted allogeneic (AAA) bone containing the bone morphogenetic protein essential for osteoinduction. A total of 96 AAA bone diaphyseal cylinders were implanted intramuscularly in 24 adult male baboons and harvested at three, six, and nine months. Histologic analysis showed that the matrix had undergone considerable resorption, particularly at six and nine months. Seventy-three implants showed variable amounts of newly formed bone at the internal and external surfaces of the chemosterilized matrix. Numerous specimens showed florid bone formation, and newly formed woven bone persisted in association with the matrix for as long as nine months. Coating the AAA bone matrix with an allogeneic fibrin-fibronectin protein concentrate prepared from fresh-frozen baboon plasma did not significantly increase the amount of induced bone. Bone formation was confirmed by intravital double tetracycline labeling of the mineralization fronts. The unequivocal demonstration of bone formation by induction in a large series of adult nonhuman primates provides evidence that long-lived higher vertebrates retain the bone-inductive proteins in the extracellular matrix of bone and the crucial set of responding mesenchymal cells capable of transformation and differentiation into osteoblastic cell lines.

Animals↗

PubMed1997

Low dosage of native allogeneic bone morphogenetic protein in repair of sheep calvarial defects.

A sheep skull trephine defect model was used to test the efficacy of allogeneic partially purified sheep bone morphogenetic protein (sBMP), extracted using a low-cost alternative technique based on 60% ammonium sulphate saturation of the guanethidine-HCI extract of pulverized bone matrix. Eight mg of partially purified sBMP was implanted in six 22-mm right-side sheep calvarial critical-size defects trephined in the diploë area using a midline incision; left-side defects implanted with an equal amount of type IV collagen served as controls. After 16 weeks the sheep were killed and the defects removed. Formation of new bone was evaluated using radiomorphometry and histomorphometry. The healing percentage in sBMP-implanted defects was 60.8 +/- 8.1% and in controls 49.8 +/- 6.7% (P < 0.05) as assessed by radiomorphometry. In cross-sectional histomorphometry, newly formed bone regenerated 50.9 +/- 15.1% in the defects with sBMP and 16.1 +/- 10.6% in controls (P < 0.01). The good result, considering the low dosage of sBMP, can be explained by the strong osteoinductivity and low immunogenicity of native allogeneic sBMP.

Ammonium Sulfate↗

PubMed2001

The use of a surgical grade calcium sulfate as a bone graft substitute: results of a multicenter trial.

In a prospective, nonrandomized, multicenter study, 109 patients with bone defects were treated with a surgical grade calcium sulfate preparation as a bone graft substitute. The calcium sulfate pellets were used in place of morselized cancellous bone graft for the treatment of patients with bone defects who usually would require grafting secondary to trauma, periprosthetic bone loss, tumor, or fusion. The calcium sulfate was used alone or mixed with other materials such as bone marrow aspirate, demineralized bone matrix, or autograft. The defects that were treated were contained and were not necessary for the stability of the bony structure. Radiographic and clinical data were collected at predetermined intervals for 12 months. At 6 months postoperatively, radiographic results for all patients showed that 99% of the calcium sulfate had been resorbed and 88% of the defect was filled with trabeculated bone. There were 13 complications; however, only four (3.6%) were attributable to the product. The results of a subgroup of 46 patients with benign bone lesions treated in the same manner are identical to the results of the overall study population. Surgical grade calcium sulfate pellets are considered a convenient, safe, and readily available bone graft substitute that yield consistent successful results.

Absorbable Implants↗

PubMedDate not supplied

Effect of local injection of activin A on bone formation in newborn rats.

In order to examine the effect of activin A on the process of bone formation, activin A was injected onto the periosteum of parietal bone in newborn rats, and the effect was compared with that of transforming growth factor (TGF)-beta. The daily periosteal injection of activin A increased the thickness of both the periosteal and bone matrix layers in a dose- and time-dependent manner. A maximal effect was obtained with 5.0 micrograms/day activin A. The time course of the effect of activin A on the periosteal thickness was similar to that of TGF-beta 1. However, the effect of TGF-beta 1 was much more pronounced and was mainly on fibroblasts and inflammatory cells. The time course of the effect of activin A on the thickness of bone matrix layer was different from that of TGF-beta 1. The effect of TGF-beta 1 reached maximum (1.8-fold) within 3 days, whereas that of activin A did not develop until day 6 and reached maximum at the end of the 12-day injection period (1.4-fold). Histological examinations revealed that both TGF-beta 1 and activin A increased the number of alkaline phosphatase-positive osteoblastic cells. These results demonstrate that periosteal injection of activin A stimulates bone formation. In addition, although the possibility cannot be ruled out that the dramatic effect of TGF-beta 1 on the periosteal layer might have affected the delivery of TGF-beta 1 to the bone surface, these observations also suggest that the mode of action of activin A may be different from that of TGF-beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗

PubMed1988

The anti-bone-resorptive agent calcitonin also acts in vitro to directly increase bone formation and bone cell proliferation.

The studies summarized in this report were intended to determine whether salmon calcitonin had direct effects on bone formation indices in vitro. The results of these investigations demonstrate acute effects of calcitonin on skeletal tissues derived from embryonic chickens to increase calvarial cell proliferation ([3H]thymidine incorporation into DNA) and bone matrix synthesis ([3H]proline incorporation into collagen, as [3H]hydroxyproline) in intact calvaria and tibiae. The effects of calcitonin on [3H]thymidine incorporation were significant at 1 mU/ml (0.08 nM; P less than 0.05), additive with respect to the action(s) of F (calcitonin increased the maximum effect of F, and F increased the effect of low dose calcitonin; P less than 0.01 for each), associated with an increase in total cell protein (r = 0.82; P less than 0.02), and inversely dependent on osteoblastic differentiation (r = -0.96; P less than 0.005). The effects of calcitonin to increase bone matrix synthesis ([3H]hydroxyproline incorporation, 139% and 155% of untreated control values for tibiae and calvaria, respectively; P less than 0.005 for each) were maximal at approximately 5 mU/ml (0.4 nM) and associated with a proportional increase in alkaline phosphatase activity in the bones (r = 0.71; P less than 0.05 for tibiae). These effects of calcitonin were not dependent on continuous exposure. [3H]Thymidine incorporation was increased in calvarial cells 16 h after a 4-h limited (inductive) exposure to calcitonin (at 3 mU/ml; P less than 0.01). [3H]Proline incorporation in embryonic chicken calvaria was also increased during 3 days of limited exposure (i.e. 4 h/day) to 10 mU/ml calcitonin (P less than 0.02). The proliferative action(s) of calcitonin was not unique to chicken osteoblastline cells. Salmon calcitonin also increased [3H]thymidine incorporation in the transformed murine calvarial cell lines MMB and MC-3T3-E1 and in primary cultures of cells prepared from newborn mouse calvaria (P less than 0.05 for each). Furthermore, these effects were observed at calcitonin doses (3-30 mU/ml) that also decreased murine bone resorption (i.e. 45Ca release from prelabeled neonatal mouse calvaria; P less than 0.01).

Alkaline Phosphatase↗

PubMed2005

Combination of vascularized outer-table calvarial bone graft based on the superficial temporal vessels and allomatrix for the repair of an orbito-frontal blow-out fracture in a child.

CASE PRESENTATION: A vascularized outer-table calvarial bone graft was used for repairing a Posnick type 2 traumatic orbito-frontal bone defect supported by the use of a calcium-based putty (Allomatrix) in a 7-year-old girl. Gaps between the donor and recipient sites were filled with Allomatrix containing demineralized bone matrix particles. Four years later there was a good cosmetic result using an artificial left eye. DISCUSSION: Orbito-frontal defects have been repaired using iso-, allo- or xenografts as well as synthetic materials. Anatomical studies have pointed to the importance of the superficial temporal vessels for the vascular supply of a graft to the calvaria. CONCLUSION: The vascularized outer-table calvarial bone graft based on the superficial temporal vessels is a reliable option for repairing bony defects in the craniofacial skeleton especially in irradiated or scarred areas where there is a paucity of well-vascularized tissues. It also has the potential for bony growth in children.

Bone Matrix↗

PubMed2004

[Is bone infection of endogenous or exogenous origin? A pathophysiological approach].

Osteomyelitis is a bacterial implant in bone matrix. Infection occurs as a result of a bacteremia, an inoculation during aseptic or orthopedic surgery, or a contiguous infectious focus. Persistent and relapsing infection may be due to three situations: underlying conditions such as diabetes mellitus or rheumatoid arthritis, presence of foreign surgical implant, and a causative bacterial strain. The pathogenesis of osteomyelitis has been explored through various experimental models, involving mostly Staphylococcus (S. aureus, S. epidermidis) and has given new insights. Bacterial adherence to implanted devices or bone matrix via surface proteins is critical for bacterial survival. Further bacterial growth depends on various mechanisms: the capacity to exhibit matrix-embedded lifestyle known as biofilm and the ability for bacterial subpopulations to switch to a dormant metabolic state known as small colony variants. In addition to bacterial factors, the presence of foreign material induces a defect in local inflammatory response partly responsible for the high susceptibility to infection.

Bacteremia↗

PubMed2005

Soft-tissue vessels and cellular preservation in Tyrannosaurus rex.

Soft tissues are preserved within hindlimb elements of Tyrannosaurus rex (Museum of the Rockies specimen 1125). Removal of the mineral phase reveals transparent, flexible, hollow blood vessels containing small round microstructures that can be expressed from the vessels into solution. Some regions of the demineralized bone matrix are highly fibrous, and the matrix possesses elasticity and resilience. Three populations of microstructures have cell-like morphology. Thus, some dinosaurian soft tissues may retain some of their original flexibility, elasticity, and resilience.

Animals↗

PubMed2005

Content of bone morphogenetic protein-4 in human demineralized bone: relationship to donor age and ability to induce new bone formation.

BACKGROUND: Bone morphogenetic proteins (BMPs) are also called growth and differentiation factors (GDFs) and form a subfamily of related proteins within the TGF-beta superfamily. BMP-4 is one ofmultifuntional growth factors with pleiotropic roles in many different cell types and is predominantly present in human bone tissue. OBJECTIVES: To analyze the content of extractable BMP-4 in human demineralized bone as a function of age. MATERIAL AND METHOD: Bone samples were ground and demineralized by exposure to 0.5 N HCl and then extracted by collagenase digestion. Extractable BMP-4 was analyzed using a commercially available enzyme-linked immunosorbent assay (ELISA). RESULTS: 63 samples of demineralized bone matrix (DBM) derived from 36 men and 27 women between the ages of 15-65 years. The extractable BMP-4 content appears to be age-dependent, with DBM from younger donors being most likely to have higher BMP-4 quantity. In addition, DBM with high osteoinductivity contained greater amounts of extractable BMP-4 than DBM samples with low osteoinductivity. CONCLUSION: The BMP-4 in demineralized bone undergoes age-related decrease that may contribute to the reduction of bone volume observed with aging.

Adolescent↗

PubMedDate not supplied

Bone aging.

Bone matrix of 28-month-old (senescent) rats, compared with 13-month-old rats, is strikingly deficient in the capacity to induce bone formation. Similarly, implants of senescent matrix into one-month-old, rapidly-growing rats (weanlings) produce more bone than in 13-month-old adult recipients, but not nearly enough to compensate for deficiency in the matrix of senile bone. Matrix prepared from the bone of 13-month-old rats also produces almost no cartilage and significantly lower yields of new bone in 28-month-old (senescent) than 13-month-old rats. These observations suggest that progressive decline in the matrix morphogenetic activity of bone occurs with time in adult life. This decline is a tissue specific index of bone aging, and may contribute to the reduction of bone mass that normally occurs with senescence.

Age Factors↗