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PubMed2000

Markers of bone turnover in bone metastases.

BACKGROUND: Bone metastases are a frequent complication of cancer disease. The evaluation of metastatic bone disease is crucial for the primary cancer staging because it will influence the therapeutic decision. The diagnosis of bone metastases usually relies on skeletal X-ray and bone scintigraphy. This latter technique is a sensitive diagnostic tool but lacks specificity. Moreover, the assessment of efficacy in the treatment of bone metastasis is difficult because the increased radionucleotide uptake does not always reflect an active metastatic area but may correspond to a bone reconstruction in patients responding to treatment. Markers of bone remodeling could help the clinician in the diagnosis and follow-up of bone metastases. METHODS: A common feature of both types of bone metastases (lytic or sclerotic) is an alteration of bone remodeling activity. The rate of formation or degradation of the bone matrix can be assessed either by measuring a prominent enzymatic activity of the bone forming or resorbing cells or by measuring bone matrix components released into the circulation during formation or resorption. They have been separated into markers of formation and resorption, but when both events are coupled and in balance, either of these markers will reflect the overall rate of bone turnover. These markers are of unequal specificity and sensitivity, and some of them have not been fully investigated yet in bone metastases. None of these markers is disease specific. RESULTS: Several studies of breast carcinoma showed increased levels of pyridinium cross-links in patients with bone metastases. However, in most studies, breast carcinoma patients without evidence of metastatic bone disease excreted pyridinium cross-links at a much higher rate than healthy controls. Similar findings have been observed with other types of primary cancer including lung, prostate, kidney, throat, and digestive carcinoma. Markers of bone formation had a low sensitivity in the diagnosis of bone metastasis, but they could be useful for prostate carcinoma, in which studies have shown that all patients without bone metastasis had normal value of bone alkaline phosphatase. Bone markers can be used for the follow-up of treatment, especially bisphosphonates therapy. Bisphosphonate infusion induces a large decrease of pyridinium cross-link level. Some studies suggest that a high level of resorption markers after treatment could reflect a resistance to the treatment. Moreover, some studies have shown that level of pyridinium cross-links before treatment could be a predictive factor of the response in multiple myeloma and prostate carcinoma. CONCLUSIONS: Bone markers have improved greatly in terms of sensitivity and specificity and could be useful for an early diagnosis of bone metastases. However, the clinical value of the use of bone markers in the diagnosis of bone metastasis has not been clearly shown yet with the possible exception of BPAL in prostate carcinoma. When bone is the only site of metastases, bone markers may be useful for monitoring patients with bone metastases. Markers of bone resorption are sensitive to changes in bone turnover induced by treatment. Bone resorption markers may be particularly useful for the follow-up of bisphosphonate treatment, which is increasingly used in the management of bone metastases.

Alkaline Phosphatase↗
PubMed1994

A light and laser scanning microscopy study of bone/hydroxyapatite-coated titanium implants interface: histochemical evidence of unmineralized material in humans.

The authors describe a light and laser scanning microscopy study of hydroxyapatite-coated titanium implants retrieved from humans. A histochemical technique, using von Kossa and basic fuchsin, allowed clear differentiation between mineralized bone and unmineralized bone matrix. The bone-hydroxyapatite (HA) interface presented variable features: in some areas the mineralized bone was directly apposed to the HA surface, while in others an unmineralized red-stained material, probably osteoid, was interposed. Laser scanning microscopy confirmed these findings showing a thin layer of fluorescent material at the interface.

Bone and Bones↗
PubMed1995

Zeta potential of bone from particle electrophoresis: solution composition and kinetic effects.

The morphology of bone may be influenced by many factors, including electromechanical ones such as electric potentials, electric fields, or zeta potentials. Stress-generated potential studies in bone and particle electrophoresis studies using calcium-deficient hydroxyapatite have shown that the zeta potential depends on the composition of the steeping fluid and steeping time. To better quantify and understand these in situ potential changes in bovine cortical bone, the effects of alterations in calcium, phosphate, and fluoride concentrations in Neuman's Fluid (NF), which simulates in vivo bone extracellular fluid, were investigated using particle electrophoresis. The zeta potential increased in magnitude with increased calcium concentration in NF in as little as 17 min. Increasing phosphate concentration in NF also increased the zeta potential magnitude. These results provide support for a structural model of the bone matrix surface-bone fluid interface, which incorporates the bone surface proper (composed of collagen, mineral, and boundary regions), stationary layer (in which ions, ionic complexes, and proteins may be adsorbed), and bone extracellular fluid. These results, coupled with those of previous studies, indicate that the protein phase probably has an important role in the determination of the physiologic zeta potential; the role of the mineral phase may also be important.

Adsorption↗
PubMed2002

Canine prostate induces new bone formation in mouse calvaria: A model of osteoinduction by prostate tissue.

BACKGROUND: Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells at metastatic sites may also lead to fractures or bone instability. Misinterpretation of new periosteal bone due to bone instability as tumor-cell osteoinduction is another disadvantage of the osteolytic models. To circumvent these problems, we have developed a model system of new bone formation in the calvaria of nude mice stimulated by normal canine prostate tissue. METHODS: Collagenase-digested normal prostate tissue was implanted adjacent to the calvaria of nude mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone microenvironment by histology, calcein uptake at sites of bone mineralization, and tartrate-resistant acid phosphatase staining for osteoclasts. RESULTS: The prostate tissue remained viable and induced abundant new woven bone formation on the adjacent periosteal surface. In some cases new bone formation also was induced on the distant or concave calvarial periosteum. The new bone stained intensely with calcein, which demonstrated mineralization of the bone matrix. The new bone formation on prostate-implanted calvaria significantly increased (1.7-fold) the thickness of the calvaria compared with control calvaria. New bone formation was not induced in calvaria of mice implanted with normal canine kidney, urinary bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced disruption of the periosteum. Osteoclast numbers in the medullary spaces and periosteum of calvaria were mildly increased (61%) in mice with implanted prostate tissue. CONCLUSIONS: This animal model will be useful for investigating the roles of prostate-derived growth factors on new bone formation in vivo.

Animals↗
PubMed1988

Isolation of growth factors from adult bovine bone.

Fetal rat calvariae synthesize transforming growth factor beta (TGF beta), beta 2 microglobulin (beta 2 m), and insulinlike growth factor I (IGF I), but, except for TGF beta, it is not known if these polypeptides are also present in adult bone tissue. Pulverized bovine bone, extracted with 0.5 N HCl and 4 M guanidine HCl and fractionated by gel filtration, was found to contain several biologically active components when tested for its effects on DNA synthesis in osteoblast-rich cell cultures. TGF beta, beta 2 m, and IGF I were identified and further purified using high performance liquid chromatography (HPLC). TGF beta, identified by a standard TGF beta bioassay or by immunoreactivity, was purified by muBondapak C18 and muBondapak CN reversed phase HPLC. beta 2 m, identified by immunoreactivity, required an additional fractionation step on a DEAE-HPLC column for complete purification. IGF I, identified by immunoreactivity, was purified by HPLC using a muBondapak C18 and a DEAE-HPLC column. Purified TGF beta, beta 2 m, and IGF I migrated as single bands on polyacrylamide gel electrophoresis with respective molecular masses of 24,000, 10,000, and 7,500. In conclusion, adult bone matrix, like fetal bone cultures, contains TGF beta, beta 2 m, and IGF I and these factors may play a role in adult skeletal remodeling.

Animals↗
PubMed2005

Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat.

Osteoprotegerin (OPG) and the receptor activator of nuclear factor (NF)-kB ligand (RANKL) are key regulators of osteoclastogenesis. The present study had the main aim of showing the localization of OPG and RANKL mRNA and protein in serial sections of the rat femurs and tibiae by immunohistochemistry (IHC) and in situ hybridization (ISH). The main results were: (1) OPG and RANKL mRNA and protein were co-localized in the same cell types, (2) maturative/hypertrophic chondrocytes, osteoblasts, lining cells, periosteal cells and early osteocytes were stained by both IHC and ISH, (3) OPG and RANKL proteins were mainly located in Golgi areas, and the ISH reaction was especially visible in active osteoblasts, (4) immunolabeling was often concentrated into cytoplasmic vacuoles of otherwise negative proliferative chondrocytes; IHC and ISH labeling increased from proliferative to maturative/hypertrophic chondrocytes, (5) the newly laid down bone matrix, cartilage-bone interfaces, cement lines, and trabecular borders showed light OPG and RANKL immunolabeling, (6) about 70% of secondary metaphyseal bone osteocytes showed OPG and RANKL protein expression; most of them were ISH-negative, (7) osteoclasts were mostly unstained by IHC and variably labeled by ISH. The co-expression of OPG and RANKL in the same bone cell types confirms their strictly coupled action in the regulation of bone metabolism.

Animals↗
PubMed2004

Transforming growth factor-beta induces osteoclast formation in the absence of RANKL.

Transforming growth factor beta (TGFbeta) is a multifunctional growth factor that is produced by many cells in bone and is abundant in the bone matrix. TGFbeta is known to regulate RANKL-induced osteoclast formation and bone resorbing activity. In this study we sought to determine whether TGFbeta could directly induce osteoclast formation by a RANKL-independent mechanism. We found that the addition of TGFbeta to cultures of human monocytes and RAW 264.7 cells (in the presence of M-CSF and the absence of RANKL, TNFalpha or IL-6/IL-11) was sufficient to induce the formation of TRAP+ and VNR+ cells, which formed actin rings and were capable of extensive lacunar resorption. The addition of osteoprotegerin or antibodies to TNFalpha and its receptors, as well as antibodies to gp130, did not inhibit lacunar resorption, indicating that TGFbeta did not act by stimulating RANKL, TNF or IL-6 production by monocytes. TGFbeta-induced osteoclast formation was qualitatively different from that induced by RANKL with numerous TRAP+/VNR+ mononuclear and small multinucleated cells being formed; these cells produced many small resorption lacunae. Our results indicate that TGFbeta, which is abundant in the bone matrix, can, in the presence of M-CSF, directly induce mononuclear phagocyte osteoclast precursors to differentiate into osteoclastic cells capable of lacunar resorption.

Actins↗
PubMed2004

The degree of mineralization is a determinant of bone strength: a study on human calcanei.

Strength of bones depends on bone matrix volume (BMV), bone microarchitecture, and also on the degree of mineralization of bone (DMB). We have recently shown in osteoporotic patients treated with alendronate that fracture risk decreased and bone mineral density increased with a parallel increase of the DMB due to prolonged secondary mineralization but without modifications of BMV or bone microarchitecture. DMB and strength were both measured at the tissue level in calcaneus bone samples taken at autopsy from 20 subjects (aged 78 +/- 8 years, 8 women, 12 men) who died suddenly without apparent bone disease. DMB parameters measured on microradiographs (mean DMB, distribution of DMB, most frequent maximum DMB value, and width at half maximum, an index reflecting the homogeneity of DMB) were compared with those reported in iliac cancellous bone samples of 43 human bones. Histomorphometric measurements of microarchitectural parameters (TbTh, TbN, and TbSp) were also measured. Compression tests were performed on contiguous samples of the same calcaneus on a universal screw-driven machine (Schenck RSA 250). A 5000-N load cell (TME, F 501 TC) measured the compressive load. The displacement was measured directly on the sample using a specific displacement transducer developed by the < > The apparent Young's modulus (E), the maximal strength (sigma(max)), and the work (W) until failure were measured. In human cancellous bone tissue, mean DMB (+/- SD) was higher in calcaneus (1.135 +/- 0.147 g/cm(3)) than in iliac crest (1.098 +/- 0.077 g/cm(3)). The mean most frequent maximum DMB values (mean DMB freq. max.) were 1.118 +/- 0.175 g/cm(3) in calcaneus and 1.108 +/- 0.095 g/cm(3) in iliac samples, and DMB was more heterogeneous in calcaneus than in iliac samples (mean width at half maximum were 0.270 +/- 0.127 versus 0.227 +/- 0.056 g/cm(3), respectively). Compression tests revealed significant positive linear correlations between DMB and both elastic modulus (r(2) = 0.69) and maximal strength (r(2) = 0.69). Correlations with DMB persisted (P < 0.003) even after adjustment for both calcified bone volume, for the Young's modulus (E), the maximal strength (sigma(max)) (r(2) = 0.44 and 0.41, respectively), and microarchitectural parameters (0.50 < r(2) < 0.56, P < 0.001). The same results were obtained with the work to fracture (W) (0.23 < r(2) < 0.46, P < 0.045). We conclude that the more the cancellous tissue was mineralized, the higher was its stiffness and compressive strength. This may explain the increase in bone strength when DMB is modified in a physiological range without necessary changes of BMV and bone microarchitecture. The impact of such modifications on fracture risk and the therapeutic implications of these data remain to be analyzed.

Aged↗
PubMed2004

Characterization of acetylcholinesterase expression and secretion during osteoblast differentiation.

Although best known for its role in cholinergic signalling, a substantial body of evidence suggests that acetylcholinesterase (AChE) has multiple biological functions. Previously, we and others identified AChE expression in areas of bone that lacked expression of other neuronal proteins. More specifically, we identified AChE expression at sites of new bone formation suggesting a role for AChE as a bone matrix protein. We have now characterised AChE expression, secretion and adhesive function in osteoblasts. Using Western blot analysis, we identified expression of two AChE species in osteoblastic cells, a major species of 68 kDa and less abundant species of approximately 55 kDa. AChE colocalised with the Golgi apparatus in osteoblastic cells and was identified in osteoblast-conditioned medium. Further analyses revealed differentiation-dependent secretion by osteoblasts, with AChE secretion levels corresponding with alkaline phosphatase activity. AChE expression by osteoblastic cells was also found to be regulated by mechanical strain both in vitro and in vivo. Finally, we investigated the possibility of a functional role for AChE in osteoblast adhesion. Using specific inhibitors, blockade of sites thought to be responsible for AChE adhesive properties caused a concentration-dependent decrease in osteoblastic cell adhesion, suggesting that AChE is involved in regulating cell-matrix interactions in bone.

Acetylcholinesterase↗
PubMed2002

New bone formation in nude mouse calvaria induced by canine prostate tissue.

Osteoblastic metastases are common in patients with advanced prostate cancer. The pathophysiology of the new bone formation at metastatic sites is not currently known, but it is hypothesized that growth factors secreted by the prostate may be involved. Unfortunately, most rodent models of prostate cancer with metastasis to bone are osteolytic and not osteoblastic. Significant osteolysis by tumor cells at metastatic sites also may lead to fractures or bone instability. Misinterpretation of new periosteal bone due to bone instability as tumor-cell osteo-induction is another disadvantage of the osteolytic models. To circumvent these problems, we have developed a model system of new bone formation in the calvaria of nude mice stimulated by normal canine prostate tissue. Collagenase-digested normal prostate tissue was implanted adjacent to the calvaria of nude mice. Calvaria were examined at 2 weeks post-implantation for changes in the bone microenvironment by histology, calcein uptake at sites of bone mineralization, and tartrate-resistant acid phosphatase staining for osteoclasts. The prostate tissue remained viable and induced abundant new woven bone formation on the adjacent periosteal surface. In some cases new bone formation also was induced on the distant or concave calvarial periosteum. The new bone stained intensely with calcein, which demonstrated mineralization of the bone matrix. The new bone formation on prostate-implanted calvaria significantly increased (1.7-fold) the thickness of the calvaria compared with control calvaria. New bone formation was not induced in calvaria of mice implanted with normal canine kidney, urinary bladder, spleen, or skeletal muscle tissue, or mice with surgically-induced disruption of the periosteum. Osteoclast numbers in the medullary spaces and periosteum of calvaria were mildly increased (61%) in mice with implanted prostate tissue. In conclusion, this animal model will be useful for investigating the roles of prostate-derived growth factors on new bone formation in vivo.

Acid Phosphatase↗
PubMed2004

Ion channels in osteoblasts: a story of two intracellular organelles.

Recent advances have highlighted a synchronous coordination of osteoblast and osteoclast activity, whereby, the osteoblast collates all signals applied to the bone and activates osteoclastic resorption. The resorption of the bone and its matrix then releases growth factors held within the matrix (bone morphogenetic proteins, insulin-like growth factors and transforming growth factors) which then stimulate the osteoblast to lay down new osteoid. In healthy adults there is a balance between bone deposition and bone loss and there is no net gain or loss, and the amount of calcium (Ca2+) ingested in the diet is equal to that which is excreted. In the early stages of life, the emphasis is on bone building and more Ca2+ is retained from the diet and more bone deposited as the skeleton matures. As we age, and, in particular in postmenopausal women, the osteoclastic activity outweighs the bone deposition and the patient loses bone becoming osteoporotic. The focus of the work reported here was to identify and dissect the various cytosolic intracellular signalling pathways within osteoblasts and establish the importance of each under different physiological conditions. In brief, two basic signalling pathways exist; one is linked with a seven transmembrane spanning protein and specific receptors for ligands (the G protein linked pathways) and one pathway is linked with protein phosphorylation especially of the tyrosine kinases. In general, G protein activity is associated with endocrine ligands such as parathyroid hormone (PTH) and (calcitonin has been linked with tyrosine kinase activity) tyrosine kinase activity is linked with adhesion of osteoblasts and recognition of the substrate to which they are attached. Our specific areas of interest are the ways in which Ca2+ activity within the cell is modified and used as a signal for further activation and possibly differential gene activation.

Bone Resorption↗
PubMed2002

Directing the expression of a green fluorescent protein transgene in differentiated osteoblasts: comparison between rat type I collagen and rat osteocalcin promoters.

The osteocalcin (OC) and a 2.3 kb fragment of the collagen promoter (Col2.3) have been used to restrict transgenic expression of a variety of proteins to bone. Transgenic mice carrying a green fluorescent protein (GFP) gene driven by each promoter were generated. Strong GFP expression was detected in OC-GFP mice in a few osteoblastic cells lining the endosteal bone surface and in scattered osteocytes within the bone matrix in long bones from 1-day-old to 6-month-old transgenic animals. Similar findings were noted in the forming tooth in which only individual odontoblasts expressed GFP without detectable expression from the dental pulp. This limited pattern of OC-GFP-positive cells contrasts with the uniform expression in the Col2.3GFP mice in which large proportion of osteoblasts, odontoblasts, and osteocytes strongly expressed the transgene. To assess transgene expression during in vitro differentiation, marrow stromal cell and neonatal calvarial osteoblast cultures were analyzed. The activity of both transgenes was restricted to mineralized nodules but the number of positive cells was lower in the OC-GFP-derived cultures. The different temporal and spatial pattern of each transgene in vivo and in vitro reveals potential advantages and disadvantages of these two transgene models.

Animals↗
PubMed2003

Bone mineral density in children, adolescents and adults with glycogen storage disease type Ia: a cross-sectional and longitudinal study.

The occurrence of (symptoms related to) osteopenia is a known complication in glycogen storage disease type Ia (GSD Ia) patients. However, only limited information is available about bone mineral density (BMD). Using dual energy x-ray absorptiometry, we studied both cross-sectional and longitudinal lumbar spine areal BMD (BMD(areal) in g/cm2), areal BMD corrected for delayed bone maturation (BMD(bone age) in g/cm2), and volumetric BMD (BMD(vol) in g/cm3). Prepubertal GSD Ia patients (n = 8) had normal BMD (median z-scores BMD(areal) -0.6, BMD(bone age) -0.5 and BMD(vol) -0.5), whereas adolescent patients (n = 12) and adult patients (n = 9) had significantly reduced BMD (BMD(areal) -2.3, BMD(bone age) -1.6, BMD(vol) -2.0, and BMD(areal) -1.9, BMD(vol) -1.5, respectively). Our longitudinal study, showing a stable BMD(areal) but a trend to a decrease in BMD(vol) in prepubertal patients during follow-up, did not clarify whether the difference in BMD between prepubertal and adolescent/adult patients reflects a diminished accretion of BMD during childhood or reflects historical differences in treatment. In adolescent and adult GSD Ia patients, BMD(areal) and BMD(vol) were reduced but stable during follow-up. Especially patients with delayed bone maturation were at risk for reduced BMD. No correlation between parameters of metabolic control and BMD could be detected. Daily calcium intake was within recommended allowances ranges. Abnormal biochemical results included hypomagnesaemia (29%), hypercalciuria (34%) and reduced tubular resorption of phosphate (21%). Although the underlying pathophysiology of reduced BMD in GSD Ia remains unsolved, metabolic control should be optimized to correct as much as possible metabolic and endocrine abnormalities that may influence both bone matrix formation and bone mineral accretion.

Absorptiometry, Photon↗
PubMed1988

Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures.

Parathyroid hormone (PTH) and prostaglandin E2 (PGE2) are physiological agonists which stimulate bone cells to resorb bone, a process by which the mineralized extracellular bone matrix is dissolved. Bone resorption has a key role in the maintenance of plasma calcium levels. It has been established that both PTH and PGE2 activate adenylate cyclase in osteoblasts, but it is apparent that (1) the two agents have qualitatively different effects on osteoblasts, and (2) the generation of cyclic AMP cannot account for all the effects of PTH on bone cell metabolism. Others have demonstrated that PTH and PGE2 may also elevate intracellular calcium levels, but the mechanism by which this is achieved has not been fully defined. Here we have investigated the effects of PTH on neonatal mouse osteoblasts in culture and shown that physiological concentrations of the hormone (50 nM) caused a small increase (22%) in total inositol phosphates accumulation, with a larger increase (40%) in inositol trisphosphate. We found that this activation occurred at lower concentration than was necessary to activate adenylate cyclase. PGE2 was a more effective activator of inositol phosphates accumulation than PTH, causing up to 300% increase in the total inositol phosphates after 30 min. Both PTH and PGE2 stimulated cyclic AMP accumulation, but the activation of adenylate cyclase by forskolin did not enhance inositol phosphates production. We conclude that both PTH and PGE2 stimulate phosphoinositide turnover in mouse osteoblasts and suggest that this mechanism may contribute to their elevation of intracellular calcium in bone cells.

Animals↗
PubMed2001

Markers of bone turnover in prostate cancer.

Prostate cancer is the most common malignancy in elderly men and is often associated with bone metastases. Although bone metastases are osteosclerotic, histological and biochemical studies clearly indicate an increase of both bone formation and bone resorption, providing the rational for using bisphosphonate as a palliative treatment in these patients. The recent development of specific and sensitive biochemical markers, reflecting the overall rate of bone formation and bone resorption, has improved the non-invasive assessment of bone turnover abnormalities in patients with prostate cancer. The immunoassays for bone-specific alkaline phosphatase and type I collagen propeptides are currently the most sensitive markers to assess bone, formation. The best indices of bone resorption are the immunoassay for the pyridinoline cross-links and the related peptides that can be measured in urine and more recently in serum. A better knowledge of the biochemistry, especially of the age-related post-translational modifications of type I collagen in the abnormal bone matrix, associated with bone metastases from prostate cancer may lead to markers of increased sensitivity. A recent example is the demonstration that the isomerization and racemization of the aspartic acid residue in C-telopeptides of type I collagen is impaired in patients with prostate cancer and bone metastases, a pattern than can be detected with specific conformational antibodies. The most sensitive markers of bone formation and bone resorption are markedly increased in patients with bone metastases compared with patients with cancer but without metastases, the levels correlating with the extent of the bone involvement. However, their sensitivity remains limited, suggesting that the currently available biochemical markers cannot be used as a surrogate for bone scintigraphy in the diagnosis of bone involvement. A few studies have suggested that the measurement of bone markers may be useful in the assessment of response to anti-endocrine therapy, although available data indicate a lower sensitivity than with prostates specific antigen. Additional longitudinal studies are required to assess the potential use of bone markers, especially to identify patients who relapse during the course of the treatment and, more specifically 3 those that result from the progression in bone metastases.Clearly, the established use of bone markers is for monitoring effects of bisphosphonate treatment. Several studies have shown a rapid decrease of bone resorption markers in patients with prostate cancer and bone metastases, the magnitude of the decrease correlating with the efficacy of the treatment in reducing bone pain. Thus, bone markers are likely to become a useful and objective tool to monitor bisphosphonate treatment and individual the therapy scheme.

Biomarkers↗
PubMed1988

Parathyroid hormone modulates transforming growth factor beta activity and binding in osteoblast-enriched cell cultures from fetal rat parietal bone.

Transforming growth factor beta (TGF-beta) is produced by bone cells, is abundant in bone matrix, and regulates bone cell biochemical processes. In osteoblast-enriched fetal rat parietal bone cell cultures, low TGF-beta doses increase DNA synthesis, whereas higher levels are less mitogenic, stimulate collagen production, and decrease alkaline phosphatase activity. Parathyroid hormone by itself has minimal effects on these processes, but it opposes the effects of TGF-beta and alters TGF-beta binding to its receptors in osteoblast-enriched cultures. Some functions ascribed to parathyroid hormone in bone may therefore result from alterations in TGF-beta activity, suggesting that the local effects of TGF-beta in bone are under systemic hormonal control.

Animals↗
PubMed1995

Bone composition and histological analysis of young and aged rats fed diets of varied calcium bioavailability.

OBJECTIVE: The effects of varied calcium bioavailability on bone development (young animal) and bone maintenance (aged animal) were evaluated by the application of bone composition and histologic/histomorphometric techniques. METHODS: Groups of male young (3-4 weeks old) and aged (24-month-old) rats were fed nutritionally-complete but calcium-restricted (0.15%) diets in which calcium was derived from spinach or nonfat dry milk (NFDM). A 0.5% calcium casein-based diet group was included as a comparison at the National Research Council's requirement level. All animals were pair-fed to the spinach-fed group. At the end of 60 days, lumbar vertebrae, tibia and femurs were harvested for bone histomorphometric and bone composition analyses. RESULTS: Histological analysis of the fifth lumbar vertebral body of the young spinach-fed group showed retarded development and mineralization of trabecular bone. Histomorphometry revealed that the spinach-fed group seemed to respond to the lower bioavailable calcium source by reducing the mineralization of bone matrix and stimulating bone resorption with a resultant decrease in bone volume (0.027, 0.059, 0.068 mm3 in spinach, NFDM and 0.5% calcium casein-based diet groups, respectively). The aged animals, however, appeared to respond to the reduction in available dietary calcium by mobilizing skeletal reserves, with a subsequent decrease in bone volume (0.057, 0.060, 0.073 mm3 in spinach, NFDM and 0.5% calcium casein-based diet groups, respectively). CONCLUSION: This study demonstrates that a low bioavailable calcium source, spinach, suppresses calcium deposition in bones of young animals resulting in a reduction in both quality and quantity of bone. Moreover, despite the stable structure of the mature bone, a low bioavailable calcium source may also compromise the skeletal integrity of the aged animal.

Aging↗