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PubMed2002

Cystatin C in milk basic protein (MBP) and its inhibitory effect on bone resorption in vitro.

A cystein protease inhibitor was identified in the basic fraction of bovine milk. We have reported in our previous study that the milk basic protein (MBP) fraction suppressed osteoclast-mediated bone resorption in vitro. Since osteoclasts secreted cystein protease to digest collagen in the bone matrix, we identified the cystein protease inhibitor in MBP. A 12-kDa inhibitor was purified from MBP by papain affinity gel chromatography and subsequent Hi-Load Superdex 75 gel filtration chromatography. The N-terminal sequence of the 18 amino acid residues of the inhibitor corresponded to bovine cystatin C. The 12-kDa cystein protease inhibitor in MBP therefore seemed to be cystatin C. Purified cystatin suppressed bone resorption with the use of isolated osteoclasts in vitro. Cystatin in MBP is suggested as one of the factors inhibiting bone resorption.

Amino Acid Sequence↗
PubMed1995

In vivo parathyroid hormone stimulates in vitro bone resorption by bovine monocytes.

Cells of the monocyte-macrophage lineage have been thought to play a role in bone resorption. We examined the effects of in vivo administration of parathyroid hormone and 1,25-dihydroxyvitamin D3 on the ability of monocytes to degrade bone in vitro. Administration of parathyroid hormone for 4 d resulted in sustained hypercalcemia and a transient 1-d increase in plasma 1,25-dihydroxyvitamin D3. Parathyroid hormone significantly stimulated bone degradation by monocytes 2.6 times more than that of pretreatment controls. Parathyroid hormone treatment significantly enhanced (threefold) release of superoxide anion by monocytes stimulated with phorbol 12-myristate 13-acetate and increased migration of monocytes to bone particles in vitro. Continuous 7-d infusion of 1,25-dihydroxyvitamin D3 (50 micrograms/d) elevated plasma 1,25-dihydroxyvitamin D3 until infusions were discontinued. Increased 1,25-dihydroxyvitamin D3 was associated with hypercalcemia, which continued for several days postinfusion. In vivo administration of 1,25-dihydroxyvitamin D3 did not affect in vitro ability of monocytes to degrade bone. We concluded that in vivo administration of parathyroid hormone enhanced in vitro responsiveness of isolated monocytes in a manner consistent with a role for monocytes in bone remodeling. Furthermore, these data suggested that circulating monocytes could be a useful experimental model for further studies on parathyroid hormone responsiveness and bone resorption for the cow with milk fever.

Animals↗
PubMed1995

Bone resorption at the femoral neck is dependent on local factors in nonosteoporotic late postmenopausal women: an in vitro-in vivo study.

Local mediators of bone resorption may be involved in bone loss in recently postmenopausal women and in osteoporosis. In the present study, we investigated the production of cytokines and the formation of osteoclast-like cells in marrow cultures from 16 late postmenopausal nonosteoporotic women (mean age: 66 +/- 8 years; time after menopause: 15 +/- 8 years) undergoing hip replacement for arthrosis. Marrow adherent mononuclear cells (MMNC) isolated from femoral diaphysis marrow were cultured for 10 days in the absence or in the presence of 1,25(OH)2D3. In vivo bone resorption was concomitantly assessed by histomorphometry on femoral neck bone sections. The number of TRAP+ multinucleated cells obtained after 10 days in MMNC cultured in the presence of 1,25(OH)2D3 correlated with the number of osteoclasts measured on the bone femoral neck biopsies (r = 0.65, p < 0.01), suggesting that the formation of multinucleated cells in vitro could reflect the osteoclast differentiation in vivo. Furthermore, the number of osteoclasts was related to the eroded volume and the trabecular separation of the femoral neck bone biopsies. Finally, the release of interleukin-1 (IL-1), IL-6, and TNF-alpha by cultures of peripheral blood mononuclear cells (PBMC) and MMNC was measured by radioimmunoassay. The cytokine levels of basal and 1,25(OH)2D3-treated MMNC decreased from days 2 to 5 and then reached a plateau to day 10. The number of TRAP+ multinucleated cells obtained after 10 days in MMNC cultures correlated with the basal IL-6 release in the same cultures determined at day 2 (r = 0.55, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1994

[Assay of urinary pyridinoline and deoxypyridinoline as potential markers of the rate of bone resorption: usefulness of urinary pyridinoline and deoxypyridinoline in patients with prostate cancer with bone metastases].

The collagen crosslinks, pyridinoline (Pyr) and deoxypyridinoline (D-Pyr), were recently identified as potential markers of the rate of bone resorption. To determine whether urinary concentrations of Pyr and D-Pyr might provide an early warning of bone metastases in patients being monitored for cancer of the prostate, we compared these two newer parameters with the conventional indicators, that is, the serum concentrations of Bone Gla protein (BGP: osteocalcin) and alkaline phosphatase (ALP), in patients with prostate cancer with and without bone metastases vs. those of age-matched patients with benign prostatic hyperplasia (BPH). Urinary excretion of these compounds, expressed as a ratio to urinary creatinine (mg/dl), was determined by high performance liquid chromatography (HPLC) in 23 patients with prostate cancer (16 with bone metastases and 7 without bone metastases) and in 23 patients with BPH. The mean values of urinary Pyr and D-Pyr; 65.02 +/- 38.16 pmol/mumol of creatinine and 8.87 +/- 7.01 pmol/mumol of creatinine and 8.87 +/- 7.01 pmol/mumol of creatinine, respectively, for patients with bone metastases of prostate cancer were significantly higher than those for patients without bone metastases of prostate cancer (27.43 +/- 10.29 pmol/mumol of creatinine and 4.24 +/- 1.88 pmol/mumol of creatinine) or for patients with BPH (25.58 +/- 7.54 pmol/mumol of creatinine and 3.52 +/- 1.07 pmol/mumol of creatinine). Among these three groups of patients, there were statistically significant (Pyr: P = 0.0001, D-Pyr: P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1997

New biochemical markers of bone resorption in the study of postmenopausal osteoporosis.

We performed a comparative study on the sensitivity of the determination of several biochemical markers of bone resorption: urinary calcium/creatinine, free pyridinolines (F-Pyr), free deoxypyridinoline (F-Dpyr), carboxyterminal telopeptide of collagen I (CTX) and aminoterminal crosslinked telopeptides of collagen I (NTX) in the study of postmenopausal osteoporosis. The study included 19 untreated osteoporotic postmenopausal women, aged 59 +/- 6 years, range 46-70 and 16 healthy control postmenopausal women, aged 56 +/- 7 years, range 48-70 years. The following bone markers were determined in 2-h fasting urine samples: calcium/creatinine (atomic absorptiometry), F-Pyr (ELISA, Metra), F-Dpyr (ELISA, Metra), CTX (Crosslaps, Cis bio International) and NTX (ELISA, Osteomark, OSTEX). Values of all markers were expressed as urinary creatinine (Cr) ratios. We found a significant increase in all the studied biochemical markers of bone resorption in osteoporotic patients with respect to control women. Areas under receiver operating characteristic (ROC) curves corresponding to F-Pyr/Cr, Calcium/ Cr, NTX/Cr, CTX/Cr and F-Dpyr/Cr were 74%, 75%, 93.4%, 95.7% and 96% respectively. There were no significant differences among the areas of the ROC curves corresponding to NTX, CTX and F-Dpyr, but areas under urinary calcium and F-Pyr were significantly lower. Among the biochemical markers of bone resorption studied, F-Dpyr, CTX and NTX presented the best discrimination between osteoporotic and control women. F-Dpyr/Cr sensitivity was 79% with a specificity of 100%, CTX/Cr sensitivity was also 79% with a specificity of 100% and NTX/Cr sensitivity was 52% with a specificity of 100%.

Aged↗
PubMed1982

The effect of force magnitude on extractable bone resorptive activity and cemental cratering in orthodontic tooth movement.

The delay period in the orthodontic tooth movement cycle was studied with respect to the stimulation of an extractable bone resorptive activity and the degree of tissue damage at sites of greatest pressure. Total area of cemental cratering was used as a measure of tissue damage. Both bone resorptive activity and tissue damage were found to be significantly increased with moderate and high forces, a fact which supports the suggestion that bone resorptive activity is related to tissue damage.

Alveolar Process↗
PubMed2004

Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts.

The proliferation inhibitor of the macrolide class, everolimus, is a drug shown to be effective in the prevention of organ transplant rejection and to have a potential in the treatment of rheumatoid arthritis and certain cancers. As these diseases or their current treatments are associated with bone loss, we examined the effect of everolimus on mouse and human bone cells in vitro and on bone in an ovariectomized (OVX) rat model. Everolimus potently inhibited primary mouse and human osteoclast activity in the pit assay (IC50 values of 0.6-4.0 nM), as well as osteoclast formation, measured as the number of tartrate-resistant acid phosphatase (TRAP) multinucleated cells (IC50 values of 7.7-10.5 nM). Inhibition of osteoblastic differentiation was also observed (IC50 value of 13.5 nM). As expected, everolimus inhibited proliferation of osteoclast precursors and stimulated apoptosis, albeit with insufficient potency and efficacy to explain inhibition of osteoclast activity. Thus, everolimus appeared to directly inhibit bone resorption, which is in accord with the detected inhibition of mRNA and protein expression of cathepsin K; the main collagen-degrading protease in osteoclasts. Despite the in vitro antiproliferative activity of everolimus and the observed inhibition of osteoblast differentiation, no detrimental effects were detected at different skeletal sites in mature OVX rats at doses up to 3 mg/kg/day. This everolimus dose also prevented the OVX-induced loss of cancellous bone by 60%, an effect predominantly associated with decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone network. Everolimus inhibited S6 kinase 1 activity in rat blood cells, skin, and bone, at doses equivalent to those used for efficacy experiments in the OVX rat model, which demonstrated in vivo targeting of the expected molecular pathway. In conclusion, everolimus directly inhibits bone resorption by osteoclasts and thus could at least be neutral or protective for bone in vivo, which would favor its use in disease indications associated with bone loss.

3T3 Cells↗
PubMed2003

Chemical sympathectomy-induced changes in TH-, VIP-, and CGRP-immunoreactive fibers in the rat mandible periosteum: influence on bone resorption.

The expression of neurotransmitter receptors by bone cells supports the concept that the nervous system is a regulator of bone metabolism. The discrimination of the respective roles of the sensory and sympathetic nervous systems requires evidence of topographic relationships between the corresponding fibers and the cells involved in bone turnover, in vivo. In this study, the influence of the sympathetic system on bone resorption was assessed by using a synchronized model of cortical resorption along the mandible. The sympathetic system was destroyed by daily injections of guanethidine (40 mg/kg) for 25 days; a resorption wave was induced on day 21. The distribution of periosteal tyrosine-hydroxylase (TH)-, vasoactive intestinal polypeptide (VIP)-, and calcitonin gene-related peptide (CGRP)-immunoreactive (IR) fibers was studied by compartmentalizing the periosteum. Most fibers were located in the distal, non-osteogenic compartment. TH-IR fibers were located perivascularly, VIP-IR fibers were gathered at the boundary with the osteogenic compartment, and CGRP-IR fibers were scattered. Sympathectomy decreased the number of TH- and VIP-IR fibers and increased the number of CGRP-IR fibers, without changing their topography. After the injection of Fast blue, a retrograde fluorescent marker, over the periosteum, fluorescent neuronal cell bodies were found in the superior cervical ganglion (SCG). Many neurons were TH-IR and very few were VIP-IR. Sympathectomy decreased the numbers of fluorescent and TH-IR cell bodies. It also decreased the number of preosteoclasts and osteoclasts, which had a drastic effect on the cortical bone surface, as assessed by scanning electron microscopy. These data indicate that VIP-IR fibers have a strategic position close to the most peripheral and less differentiated, osteogenic cells, pointing to a functional relationship. As poorly differentiated osteogenic cells support preosteoclast differentiation, VIP-IR fibers may be involved in this process, as suggested by the smaller number of preosteoclasts in sympathectomized rats. Although VIP is predominantly a parasympathetic mediator, it seemed to be conveyed by sympathetic fibers, as shown by the marked effect of guanethidine treatment. Nevertheless, these fibers did not originate from the SCG, contrary to TH-IR fibers.

Adrenergic Fibers↗
PubMed2003

Dose dependent effects on bone resorption and formation of intermittently administered intravenous ibandronate.

The aim of the present paper was to delineate in detail the dose-dependent effects of intermittent intravenous (IV) ibandronate treatment on the dynamics of markers of bone resorption and formation. The study included 73 healthy postmenopausal women between 50 and 70 years of age. Two groups received an IV injection of either 1 mg or 2 mg ibandronate on day 0 and 84 and one group, which received no treatment, served as control. Study duration was 168 days. Bone turnover was estimated by measuring the serum concentration of the C-terminal collagen I telopeptide (s-CTx, bone resorption) and osteocalcin (s-OC, bone formation) at 19 consecutive time-points. Serum CTx decreased rapidly reaching a nadir 7 days after drug administration. Maximal changes from baseline in the 1 and 2 mg ibandronate groups were -81% and -90%, respectively ( P<0.001). However, already 2 weeks after drug administration, s-CTx started to rise again in both treatment groups, reaching -16% and -20% by day 84, i.e. immediately before the second drug administration. In contrast, s-OC showed a slower but progressive decrease over time reaching a nadir at -35% inhibition after 5 months. On a group level, the suppression of bone resorption was greater or equal to the suppression of bone formation at all time points. However, the least significant change (LSC) analysis performed at the individual level highlighted individuals who at certain time points showed apparently greater suppression of formation than resorption, which could also contribute to the inefficacy of this dosing regime. Although the physiological relevance of this latter finding would require further analysis, the results draw attention to the need to optimize the intermittent IV dosing of ibandronate in order to approximate more closely the sustained and balanced anti-resorptive effect provided by daily oral treatment.

Aged↗
PubMed2000

Expression of the proteinase specialized in bone resorption, cathepsin K, in granulomatous inflammation.

BACKGROUND: The cysteine proteinase cathepsin K has aroused intense interest as the main effector in the digestion of extracellular matrix during bone resorption by osteoclasts. The enzyme is not a housekeeping lysosomal hydrolase, but is instead expressed with striking specificity in osteoclasts. In this work, we present evidence for the association of cathepsin K with the granulomatous reaction. Granulomas are inflammatory tissue reactions against persistent pathogens or foreign bodies. We came across cathepsin K while working on Echinococcus granulosus, a persistent tissue-dwelling, cyst-forming parasite that elicits a granulomatous response. MATERIALS AND METHODS: The walls of hydatid cysts from infected cattle were solubilized. Strong proteolytic activity was detected in the extracts. The proteinase responsible was purified by anion exchange and gel filtration. The purified protein was subjected to N-terminal sequencing, and its identity further confirmed by Western blotting, with a cathepsin K-specific antibody. The same antibody was used to localize the proteinase in paraffin-embedded sections of the parasite and the local host response. RESULTS: A proteinase was purified to near homogeneity from hydatid cyst extracts. The enzyme was unequivocally identified as host cathepsin K. Both the proenzyme and the mature enzyme forms were found. Cathepsin K was then immunolocalized both to the parasite cyst wall and to the epithelioid and giant multinucleated cells of the host granulomatous response. CONCLUSIONS: In the granulomatous response to the hydatid cyst, cathepsin K is expressed by epithelioid and giant multinucleated cells. We propose that, by analogy with bone resorption, cathepsin K is secreted by the host in an attempt to digest the persistent foreign body. Both processes, bone resorption and granulomatous reactions, therefore tackle persistent extracellular material (the bone matrix or the foreign body), and utilize specialized cells of the monocytic lineage (osteoclasts or epithelioid/giant cells) secreting cathepsin K as an effector.

Amino Acid Sequence↗
PubMed2000

Analysis of skeletal development on the basis of body mass and bone resorption.

Regression analysis was utilized to define the relationships among body weight, whole skeleton bone resorption (3H-tetracycline method), and the development of skeletal mass. The results indicated that skeletal development (% body weight) of slowly growing, 24-week-old rats consisted of two major components, one directly (r = 0.985, P<0.001) and one inversely (r = 0.977, P<0.001) related to body weight. It was further noted that the skeletal resorption rate was inversely correlated to body weight (r = 0.879, P<0.05) and directly related to skeletal development (r = 0.865, P<0.05), suggesting that whole skeleton bone resorption and formation were highly correlated in the slowly growing animal. A third small component of skeletal development identified in the analysis of data from 24-week-old animals, showed no direct relationship to either body weight or resorptive activity. The model presented enables the separation of skeleton mass into major components which may represent mechanically and metabolically driven bone formation.

Animals↗
PubMed2004

Mechanism of acid-induced bone resorption.

PURPOSE OF REVIEW: This review presents our current understanding of the way metabolic acidosis induces calcium efflux from bone, and in the process, buffers additional systemic hydrogen ions associated with acidosis. RECENT FINDINGS: Acid-induced changes in bone mineral are consistent with a role for bone as a proton buffer. In response to metabolic acidosis in an in-vitro bone organ culture system, we observed a fall in mineral sodium, potassium, carbonate and phosphate, which each buffer protons and in vivo should increase systemic pH towards the physiologic normal. Initially, metabolic acidosis stimulates physicochemical mineral dissolution and subsequently cell-mediated bone resorption. Acidosis suppresses the activity of bone-resorbing cells, osteoblasts, decreasing gene expression of specific matrix proteins and alkaline phosphatase activity. There is concomitant acid stimulation of prostaglandin production by osteoblasts, which acting in a paracrine manner increases synthesis of the osteoblastic receptor activator of nuclear factor kappa B ligand (RANKL). The acid induction of RANKL then stimulates osteoclastic activity and recruitment of new osteoclasts to promote bone resorption and buffering of the proton load. Both the regulation of RANKL and acid-induced calcium efflux from bone are mediated by prostaglandins. SUMMARY: Metabolic acidosis, which occurs during renal failure, renal insufficiency or renal tubular acidosis, results in decreased systemic pH and is associated with an increase in urine calcium excretion. The apparent protective function of bone to help maintain systemic pH, which has a clear survival advantage for mammals, will come partly at the expense of its mineral stores.

Acidosis↗
PubMed1989

Bone resorption and circulating PTH-like bioactivity in an animal model of hypercalcaemia of malignancy.

An in vivo model of humoral hypercalcaemia of malignancy has been used to examine the role of circulating PTH-like bioactivity in the development of bone resorption and hypercalcaemia. After inoculation of cells from a renal carcinoma cell line into nude mice, circulating PTH-like bioactivity as measured by the sensitive renal and metatarsal cytochemical bioassays for PTH was elevated in only 18% and 53% of the mice respectively. Bone resorption was elevated in all the mice investigated irrespective of the level of PTH-like bioactivity. Thus, in this model, while the circulating PTH-like moiety is more potent when acting on bone, it did not correlate with the degree of bone resorption suggesting that it may not be the sole cause of the hypercalcaemia.

Animals↗
PubMed1991

Structural requirements for the action of parathyroid hormone-related protein (PTHrP) on bone resorption by isolated osteoclasts.

Parathyroid hormone-related protein (PTHrP) plays a major role in the syndrome of humoral hypercalcemia of malignancy (HHM) by its actions on bone and kidney. In this study an isolated osteoclast bone resorption assay was used to investigate the actions of this peptide and the structure-activity relationships for its resorption effect. As with PTH, neither synthetic nor recombinant PTHrP preparations stimulated resorption within highly purified osteoclast populations. Resorption was stimulated only in the presence of contaminating osteoblasts or in cocultures with the osteoblast-like cell line UMR-106. In the presence of osteoblasts PTHrP-(1-34) and PTHrP-(1-84) stimulated bone resorption in a dose-dependent manner with a potency comparable to that of PTH-(1-34) on a molar basis. The biologic activity of the PTHrP was shown to reside in the first 34 amino acids, and within that region the structural requirements for promotion of osteoclastic resorption resembled closely those for promotion of cyclic AMP formation in osteoblast-like cells. Using emulsion autoradiography with iodinated PTHrP-(1-34) and PTHrP-(1-84) on mixed bone cell preparations from neonatal rats, specific binding was demonstrated only to osteoblasts, not to osteoclasts. These results clearly demonstrate that PTHrP is a potent stimulator of bone resorption and that these effects are, like those of PTH, mediated by initial actions upon cells of the osteoblast lineage.

Animals↗
PubMed2001

Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria.

Prostaglandins (PG) E1, E2 and F2alpha induce bone resorption in isolated neonatal parietal bone cultures, and an associated increase in interleukin-6 (IL-6) production. Indomethacin had little effect on the response to PGE2, or the relatively non-selective EP receptor agonists 11-deoxy PGE1 and misoprostol, but blocked the effects of PGF2alpha and the F receptor agonist fluprostenol, indicating an indirect action via release of other prostaglandins. It is more likely that there is positive autoregulation of prostaglandins production in this preparation mediated via stimulation of F receptors. The effects of selective EP receptor agonists sulprostone (EP1,3) and 17-phenyl trinor PGE2(EP1), indicated the involvement of EP2 and/or EP4 receptors, which signal via cAMP. The relatively weak increase in IL-6 production by misoprostol (with respect to resorption) suggests that these responses are controlled by different combination of EP2 and EP4 receptors. The PKA activator, forskolin, induced small increases in bone resorption at lower concentrations (50-500 ng/ml) but a reversal of this effect, and inhibition of resorption induced by other stimuli (PTH, PGE2), at higher concentrations (0.5-5 microg/ml). IL-6 production was markedly increased only at the higher concentrations. The inhibitory effect of forskolin may be a calcitonin-mimetic effect. PMA induced both resorption and IL-6 production which were both blocked by indomethacin, indicating a role for PKC in the control of prostaglandin production.

Alprostadil↗
PubMed1995

[Inhibitory effects of bisphosphonates on bone resorption].

Bisphosphonates have a P-C-P bond instead of the P-O-P bond of inorganic pyrophosphate that makes them resistant to enzymatic degradation and gives them a high affinity for hydroxyapatite. They are potent blockers of osteoclastic bone resorption and have been successfully used to treat metabolic bone diseases that involve increased bone resorption. It is possible to synthesize a variety of bisphosphonates by substituting the hydrogen on the carbon atom. The pharmacological characteristics and activity varies greatly from compound to compound, ranging from 1 to 10,000. Some structure-activity relationships have been found, but no clear-cut one has been established yet. There is a general consensus that the inhibition of bone resorption by bisphosphonates is not caused by the inhibition of dissolution of the hydroxyapatite crystal, but is actually caused through a cellular mechanism that is not completely understood. In the present review article, the possible mode of bisphosphonate action was discussed with special reference to: (1) whether bisphosphonates inhibit the function of mature osteoclasts directly or through osteoblasts and (2) whether bisphosphonates inhibit the proliferation or differentiation of osteoclast progenitors to osteoclasts.

Animals↗
PubMed2004

Characterization of aged osteocalcin fragments derived from bone resorption.

INTRODUCTION: Osteocalcin (OC) is a small bone matrix protein exclusively found in mineralized tissue. OC measured in serum or plasma provides an index of bone formation. In the present study a sensitive inhibition ELISA was established that could quantify fragments derived from the OC Mid-region in human urine. METHODS: The ELISA was based on a monoclonal antibody directed against residues 21-29 of human OC (Mid-OC Urine ELISA). OC fragments were isolated from human urine by immunoaffinity chromatography. OC fragments were purified further by reversed phase high performance chromatography for characterization by N-terminal sequencing and mass-spectrometry. OC fragments were assayed in bone cell culture supernatants and in serum and urine from patients undergoing anti-resorptive bisphosphonate therapy using the Mid-OC urine ELISA. RESULTS AND CONCLUSION: It was demonstrated that the release of OC fragments was highly correlated with osteoclast-mediated pit formation (r2= 0.89) and with an established marker of bone resorption (CTX; r2=0.91). Mid-OC values were decreased markedly after 3 and 10 days of anti-resorptive bisphosphonate treatment further indicating that the marker reflects bone resorption. The molecular characterization revealed that most of these molecules were less than 15 amino acids in length and many contained modified aspartyl residues (D-aspartyl and isoaspartyl) characteristic of aged proteins. The presence of such modifications shows that these molecules have resided in the bone matrix for an extended period and thus they cannot be derived directly from bone formation. In conclusion, these findings demonstrate that OC-fragments are released during osteoclastic bone resorption and that the quantification of specific age-modified OC fragments can provide an index of bone resorption.

Adult↗
PubMed1997

Cellular and molecular strategies for studying the regulation of bone resorption using the toothless (osteopetrotic) mutation in the rat.

The division of labor among cells of the skeleton is distinct and diverse and the regulation of these cells is interdependent. Osteoclasts are the cellular source of bone resorption and signals for their development and activation come, at least in part, from bone and other cells in the local environment. Studies of isolated cells have identified some factors in the developmental cascade of osteoclasts but there is little understanding of the sequence and local concentrations, not to mention other factors, needed for both the development of competent osteoclasts and for coordinated bone resorption. We review the skeletal biology of one osteopetrotic mutation in the rat, toothless, in which bone resorption is severely reduced because of a failure in the development and function of osteoclasts. Furthermore, we review the advantages and limitations of a relatively new method, differential display of mRNA (DD), that identifies differences in gene expression in two or more populations of cells. We present a strategy and preliminary data for the application of DD to this mutation. We propose that application of this method to these and other skeletal diseases, with the appropriate controls and confirmations, will provide data about pathogenetic pathways and has a high probability for identifying new regulators of skeletal development and turnover.

Animals↗