Bone Remodeling Sequence Research Articles

Calcium homeostasis: Reassessment of the actions of parathyroid hormone

The purpose of this report is to adjust our interpretation of the actions of parathyroid hormone (PTH) to include its action on the bone mineral–noncollagenous protein interactions at all bone surfaces. The three primary areas that respond to PTH are: (1) all bone surface areas in contact with the extracellular fluid (ECF), (2) the kidney, and indirectly the intestinal tract, and (3) the bone remodeling sequence. The primary rapid action of the hormone is to set and maintain the free calcium concentration of the ECF. This it does by raising the equilibrium level at bone mineral surfaces. It affects the noncollagenous protein bone mineral process to raise the free calcium level in the ECF from the base level of 3.5 mg/100 ml to the physiological level of 5.0 mg/100 ml. Maintaining the higher level requires continuous secretion of parathyroid hormone. The action of PTH at bone surfaces tends to be catabolic in nature in regard to bone loss. The hormone also acts on the kidney to raise the threshold for calcium reabsorption and by stimulation of renal hydroxylation of vitamin D to increase intestinal absorption of calcium. Its action here is to supply the ECF with calcium derived from food intake. This is the extent of PTH action on renal processes. PTH acts on all three steps in the bone remodeling process. While its total function here is not clear, the result is a net increase in the synthesis of collagen. The report concludes by comparing the actions of PTH as proposed here to the functions of PTH that have been proposed in the past.

Changes in Biochemical Markers after Lower Limb Fractures

The bone remodeling sequence after bone fracture changes the concentrations of biochemical bone markers, but the relationships of fracture size and of healing time to changes in biomarkers are unclear. The present pilot study was undertaken to determine the changes found in serum bone markers after plate osteosynthesis of closed distal tibial and malleolar fractures during a study period of 24 weeks. We measured tatrate-resistant acid phosphatase (TRACP 5b), collagen type I C-terminal telopeptide (ICTP), bone-specific alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I C-terminal propeptide (PICP), procollagen type III N-terminal propeptide (PIIINP), and human cartilage glycoprotein 39 (YKL-40) in 20 patients with lower limb fractures (10 malleolar, 10 tibia). A physical examination and radiographs were completed to assess evidence of union. All malleolar fractures healed within 6 weeks, whereas 2 tibial fractures did not show complete bone healing after 24 weeks. Changes were comparable but more pronounced in the tibia group, and marker concentrations remained increased at the end of study (bone ALP, 86 vs 74 U/L; OC, 14.9 vs 7.7 microg/L; ICTP: 5.6 vs 3.3 microg/L at day 84 after osteosynthesis, P <0.05 in tibia; 80 vs 70 U/L, 8 vs 5.2 microg/L, and 3.5 vs 3.2 microg/L, respectively, in the malleolar fracture group). In normal bone healing, changes in bone turnover markers were primarily dependent on the fracture size. Delayed tibia fracture healing may involve a disturbance in bone remodeling.

Opg, RANKl, and RANK in cancer metastasis: expression and regulation.

In normal adult human bone, the skeleton is renewed on a continuous basis in a dynamic, highly regulated process known as the bone remodeling sequence. The synthesis of new bone by osteoblasts is consequent to the critical primary step of excavation of old bone (resorption or osteolysis) by large multinucleated osteoclasts. These processes are tightly coupled such that, in normal bone homeostasis, the formative and resorptive phases are balanced [reviewed in (Mundy, 1999)].KeywordsBone ResorptionGiant Cell TumorSkeletal MetastasisHuman Bone Marrow Stromal CellBiophysical Research CommunicationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Microstructure of the trabecula and cortex of iliac bone in primary hyperparathyroidism patients determined using histomorphometry and node-strut analysis.

The purpose of this study was to use histomorphometry to compare the microstructure of trabecular and cortical bone in patients with primary hyperparathyroidism (PH) with that seen in osteoporosis. Histomorphometric and node-strut analyses of iliac bones were performed on 11 female patients with PH (61.3 +/- 8.0 years old) and 61 age-matched female patients with involutional osteoporosis (OP) (63.6 +/- 5.6 years old). Cancellous bone volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and wall thickness (W.Th) were not significantly different in these two groups. The bone formation rate (BFR) tended to be higher in the PH group than in the OP group. The number of nodes (N.Nd/TV) and node-to-node strut length (Nd.Nd/TV) were significantly higher in the PH group than in the OP group. The number of termini (N.Tm/TV) and terminus-to-terminus strut length/total strut length (Tm.Tm/TSL) were significantly lower in the PH group; cortical porosity was significantly higher in the PH group than in the OP group. No correlation was found between age and N.Nd in the PH group, but there was a negative correlation between age and N.Nd in the OP group. Our results show that trabecular connectivity was maintained while cortical porosity deteriorated in patients with PH compared with OP. These results suggest that there are microstructural differences between PH and OP in cancellous and cortical bone that result from the bone remodeling sequence in humans.

Osteopontin at mineralized tissue interfaces in bone, teeth, and osseointegrated implants: ultrastructural distribution and implications for mineralized tissue formation, turnover, and repair.

Currently available data describing the gene expression and regulation, secretion, distribution, and protein chemistry of osteopontin (OPN) all are consistent with the notions of this protein functioning as an inhibitor of mineralization and/or as a mediator of cell-matrix and matrix-matrix/mineral adhesion (cohesion) during the formation, turnover, and repair of normal and pathological mineralized tissues. The properties and overall integrity of mineralized tissues are in part dictated by the nature of their interfaces--sites where organic and inorganic components of the extracellular matrix interact to provide biomechanical strength, regulate mineral ion homeostasis, and influence cellular events involved in mineralized tissue modeling, remodeling, and repair. High-resolution, colloidal-gold immunocytochemistry has been used to characterize the proteinaceous composition of these interfaces and to establish that the phosphorylated sialoprotein, OPN, is a major component found at these sites where it accumulates as a dense, planar "coating" of organic material termed either a cement line or a lamina limitans. Structural/functional features of OPN predict an ability of this protein to regulate calcification in the matrix proper of mineralized tissues and to participate, more specifically, in cell-matrix and matrix-matrix/mineral adhesion in laminae limitantes and cement lines, respectively. From the ultrastructural immunocytochemical data presented herein for OPN illustrating the cellular expression and extracellular matrix distribution of this protein, it is demonstrated that the production of OPN is one of the earliest, and latest, secretory activities of the osteoblast lineage and that this activity manifests itself morphologically as a cement line or a lamina limitans, respectively, at bone matrix interfaces. In laminae limitantes at bone surfaces, OPN appears to be involved in osteoclast adhesion and possibly haptotaxis. An OPN-containing cement line is also present at hard tissue interfaces in rat tooth, against osseointegrated titanium and hydroxyapatite implants and at the margins of surgically created bone defects--and there may influence biological adhesion in a manner similar to that proposed for normal bone. It is suggested, therefore, that in addition to its potential for influencing cell adhesion/dynamics in bones and teeth, OPN in cement lines may act as an interfacial adhesion promoter between apposing substrates, therein maintaining the overall integrity of bone during the bone remodeling sequence and "bonding" dissimilar tissues (or biocompatible materials) together in biological composites such as teeth and osseointegrated implants.

Osteopontin and the bone remodeling sequence. Colloidal-gold immunocytochemistry of an interfacial extracellular matrix protein.

Relative to other noncollagenous, extracellular matrix proteins in mineralized tissues, colloidal-gold immunocytochemistry has demonstrated that the ultrastructural distribution of osteopontin (OPN) is unique in that this protein preferentially accumulates at mineralized tissue interfaces. In bone, this protein is present as a major component of cell-matrix and matrix-matrix interfacial structures called cement lines and laminae limitantes. In the present article, the implications of this distinct tissue distribution are discussed in terms of the bone remodeling sequence, and a detailed account of the secretion, accumulation and potential role of OPN is presented and related to current theory on the cellular and extracellular matrix events associated with basic multicellular unit (BMU)-based bone remodeling. In this context, a proposal is made describing the production of this protein as one of the earliest, and latest, secretory activities of the osteoblastic lineage, and that this activity manifests itself morphologically as a cement line ('plane') and a lamina limitans, respectively, at bone matrix interfaces. When integrated with other, known functional characteristics of this protein, the present morphological and compositional data indicate that OPN in cement lines and laminae limitantes may participate in initial and late extracellular matrix organization and mineralization, matrix-matrix/mineral adhesion and/or cell adhesion at bone interfaces.

Effects of prostaglandin inhibition on the bone activities associated with the spontaneous drift of molar teeth in the rat.

Little is known about local bone regulation that enables spontaneous molar tooth drift. In this study the role of prostaglandins (PGs) were investigated in the rat by inhibiting PG-synthesis with indomethacin (7 mg/kg/d). Untreated animals were killed at the start of the experiment, while treated ones were killed after 3, 7, or 14 days of treatment. Mandibles were processed for histomorphometry without demineralization. Changes in osteoclasts and extent of the different steps of the bone remodeling sequence (resorption, reversal, and formation) were assessed along the remodeling side of the socket of the buccal root of the first molar. The total number of osteoclasts decreased after 7 days of PG inhibition (P < 0.01 vs controls) and then partially recovered. This change was due to a sharp decrease in active cells on day 7 (P < 0.01), while inactive cells remained unchanged throughout the experimental period. The extent of resorption fell on day 7 (P < 0.01) and then recovered almost to the control level on day 14. Reversal at first increased insignificantly and thereafter decreased (P < 0.02) for the remaining 7 days. Formation was modified only on day 14; at that time it had doubled compared with controls. These results show that PGs are involved in the local regulation of bone remodeling accompanying tooth drift. Resorption inhibition was partial, indicating that other factors participate with PGs in this regulation; in addition, the trend to recovery observed at the end of the experimental period suggests that these factors can take over from PGs to achieve the necessary remodeling of the socket.

Coupling of resorption and formation on bone remodeling sequence in orthodontic tooth movement: A histochemical study

Rat's molars were submitted to orthodontic tooth movement. Bone formation areas were detected using lead-labeling technique. Osteoclasts and osteoblasts were detected by enzyme histochemistry using Tartrate resistant Acid phosphatase (TRACPase) and Alkaline phosphatase (ALPase) to determine simultaneously and mark the 2 types of cells on a same section. The sites selected for study were pressure/distal, tension/mesial and transitional areas of second molars. The results showed that: orthodontic force activated bone remodeling sequence throughout the alveolar bone; slight new bone formation was observed on the cement line on the pressure side. ALPase-positive cells were detected on the pressure side neighboring osteoclasts. On the tension side, bone formation was enhanced in the protrusions whereas both resorption and formation were observed in the depressions. In the transitional area, cellular sequence from osteoclastic bone resorption to bone formation was revealed over the cement line. These findings demonstrated that: coupling phenomena occur on the pressure side but with inhibited osteoblast activity. Bone formation on the tension side involves both promotion of bone formation by the traction force; bone remodeling sequence is established on the tension side by the interaction between osteoclastic bone resorption and bone formation that takes place in the depressions; Coupling phenomena occur in the transitional area as well. Our findings on the pressure side led to the consideration that osteoblastic cells in periodontal ligament would be involved in the regulation of osteoclastic bone resorption.

New Concepts in Bone Metabolism: Clinical Implications

All of the common diseases of bone, as well as the bone changes seen with aging, are superimposed on the normal bone remodeling sequence.... In some common bone diseases, the balance between the processes of resorption and formation remains normal, but the rate of bone turnover is much higher.

Glucocorticoid-Induced Osteoporosis: Mechanisms for Bone Loss; Evaluation of Strategies for Prevention

Osteoporosis is a common complication of chronic glucocorticoid therapy, especially in older patients who already are at risk of having a reduced bone mass. Glucocorticoids cause bone loss by altering the bone remodeling sequence: bone resorption by osteoclasts is increased, and bone formation by osteoblasts is decreased. Serum levels of osteocalcin, a protein made by osteoblasts, are decreased with glucocorticoid therapy, further evidence of decreased osteoblast function. Glucocorticoids decrease calcium absorption by the gastrointestinal tract and increase renal calcium excretion. Several recent studies suggest that low-dose glucocorticoid therapy is not associated with bone loss. Calcium supplementation with vitamin D is recommended. Several short-term studies have shown prevention of glucocorticoid-induced bone loss with bisphosphonates, calcitonin, and progesterone. Long-term clinical trials should be undertaken to determine strategies to prevent this type of osteoporosis.

CONTROL OF POSTNATAL BONE GROWTH

This article is divided into the following segments: Bone Growth—Some generalities about its definition as well as types of bone growth and their relationship to other organ systems. Structural and Functional Aspects of Bone Growth—Discussion of postnatal endochondral and intramembranous osteogenesis as well as differentiation of the concepts of bone modeling and remodeling. Control of Bone Growth-Discussion of systemic (e.g., genetic) and local factors (e.g., hormones, EGF, etc.) affecting osteogenesis as well as their effect on the bone remodeling sequence (ARF). In the final segment–Future Areas of Osteogenic Research-Future nutritional requirements, genetic engineering, as well as emerging cellular and tissue mechanisms are highlighted. Published research from 1862 to present is integrated into this author's understanding about bone growth as well as how it may be focused in the future.

実験的歯周炎の骨形成速度に及ぼす影響についての骨形態計測学的研究

Periodontitis results from the extension of the inflammatory process initiated in the gingiva to the supporting periodontal tissues, which is characterized by alveolar bone loss. To understand this bone status is needed to examine the bone dynamics of the alveolar bone involved in periodontitis. Experimental periodontitis in dogs activates remodeling in the cortex and on the surface of alveolar bone, although the bone loss occurred in periodontitis. This bone loss results from bone remodeling alteration between resorption and the succeeding formation, that is, the volume newly formed is not equal to the volume resorbed. The volume formed will depend on three variables, namely 1) the area, 2) the speed, and 3) the period of formation. The area of formation, that is, the length of osteoid surface on the alveolar bone and the number of formative osteons in the alveolar cortex, increases with inflammation. Therefore the cause of the decreased volume of newly formed bone is suggested for the dynamics of the latter two variables. This study was designed to determine the effect of experimental periodontitis on the speed of formation (the appositional rate) following resorption of the alveolar bone remodeling sequence with histomorphometry. Periodontitis was induced around the second, third and fourth premolars on the left side of the mandible in 6 male dogs by ligating a nylon floss around the teeth and into the gingival sulcus for 22 days. The right side on which ligature was not applied served as the control. Evaluation of the dynamics of appositional bone growth was facilitated by subcutaneous administration of Calcein and oxytetracycline. Administration began on Day 0 of the start of the study with the use of a schedule of 2 days on (Calcein), 8 days off, 2 days on (Calcein), 8 days off, and 2 days on (oxytetracycline). The dosage was about 10 mg/kg/day for Calcein and 20 mg/kg/day for oxytetracycline. After killing the dogs, the specimens were prepared for bone histomorphometry. Morphometric measurement was taken at the alveolar bone with the microcomputer-based system. The following measurements for alveolar cortex were made : 1) the osteoid seam thickness (OST), 2) the osteoid seam volume (OSV), 3) the circumference of osteoid seam (Sf), 4) the mineral appositional rate in microns per day in 1st half and 2nd half of the experimental period per triple labeled osteon (Mo1 and Mo2 respectively), and 5) the circumference of label per triple labeled osteon (Sl). For evalluation, several scatter diagrams were illustrated. The results were as follows : 1. OST and OSV showed significantly positive correlationship with Sf both in the inflamed and in the control side in all six dogs. 2. Mo showed significantly positive correlationship with Sl respectively in 1st half and in 2nd half of the experimental period in the inflamed side of all six dogs and in the control side except one dog whose data was insufficient. 3. In alveolar bone, the matrix appositional rate (Mf) was shown to equal Mo as in long bones, and the following relationship was found between the appositional rate (M) and the circumference of Haversian canal or osteon (S) : M=α・log S-β (α, β : constant). 4. OST and Mo2 were higher in values in the inflamed side than in the control side, and so both appositional rates, that is, Mf and Mo, were shown to increase with inflammation. 5. This increase of both appositional rates with inflammation was higher in the larger osteon, large in size earlier in the formation phase of the remodeling sequence, and was shown possibly to be the highest on the alveolar bone surface. These results suggest that the bone formation is not depressed but activated at the cellular level and the tissue level, and the activated remodeling sequence may be accelerated in the cortex and on the surface of alveolar bone in periodontitis. Alveolar bone loss would be caused by considerably shorter period of

The cellular basis of bone remodeling: the quantum concept reexamined in light of recent advances in the cell biology of bone.

The cellular basis of the normal bone remodeling sequence in the human adult is discussed in relation to a cycle of five stages--quiescence, activation, resorption, reversal, formation, and return to quiescence. Normally, 80% or more of free bone surfaces are quiescent with respect to remodeling. The structure of the quiescent surface comprises 5 layers; listed in order out toward the bone marrow these are: the lamina limitans (the electron dense outer edge of the mineralized bone matrix), unmineralized connective tissue that may be confused with osteoid by light microscopy, flattened lining cells of osteoblast lineage separated by narrow gaps, more unmineralized connective tissue, and finally either the squamous sac cells of red marrow or the cytoplasm of fat cells of yellow marrow. Activation requires the recruitment of new osteoclasts derived from precursor cells of the mononuclear phagocyte system (and so ultimately from the hematopoietic stem cell), a method for precursor cells to penetrate the cellular and connective tissue barrier of the quiescent surface, and so gain access to the bone mineral, and mechanisms for their attraction and binding to the mineralized surface, possibly in response to chemotactic signals released from bone matrix or mineral. Each of these three steps is probably mediated in some way by lining cells. Resorption is carried out by osteoclasts, most of which are multinucleated. The mean life span of individual nuclei is about 12.5 days; the additional nuclei needed to sustain resorption may be derived from local as well as blood-bone precursors, but nothing is known of their fate.(ABSTRACT TRUNCATED AT 250 WORDS)

Reconstruction of the formative site in iliac trabecular bone in 20 normal individuals employing a kinetic model for matrix and mineral apposition

A stereologic procedure for the reconstruction of matrix and mineralized bone growth curves at formative sites in trabecular bone is presented. Iliac crest bone biopsies obtained from twenty normal individuals after tetracycline double-labeling were investigated histomorphometrically. Corresponding values for osteoid width and apparent distance between bone markers and width of mineralized bone walls were classified using a sector plotting system. Observed structure widths were converted to three-dimensional structure thicknesses by a stereologic unfolding procedure. Osteoid thickness, calcification rate, and fractional labeling of osteoid varied characteristically with increasing wall thickness and permitted the construction of curves describing the time-dependent variations in matrix and wall thicknesses. The mean thickness of completed walls was 61.9 ± 1.5 μm (SE), and the mean bone formation period (Sigma f) was 145 days (124–168; 95% confidence interval.). The initial appositional rates for bone matrix (2.1 μm 3/μm 2/day) (1.4–2.9) and bone mineral (1.1 μm 3/μm 2/day) (0.4–1.9) declined gradually toward zero at the end of Sigma f. The initial mineralization lag time was 15 days (12–24) and increased to a maximum of 27 days during the first 45% of Sigma f. Thereafter, it decreased gradually toward zero. The height of the osteoblast nuclei gradually declined from 6.7 ± 0.5 μm at the start of bone formation to 1.2 ± 0.1 μm at the end. The study demonstrates that it is possible to reconstruct growth curves for trabecular bone walls based on three-dimensional values for structure thicknesses using different sections for light and fluorescence microscopy and avoiding classification according to osteoblastic nuclear morphology. This more detailed description of the bone remodeling sequence is important for the planning of treatment of different metabolic bone diseases. The techniques described make it possible to assess bone mineral balance at the BMU level and may give further insight into the mechanisms by which different hormones and drugs influence bone remodeling.

An electron-microscopic study of the bone-remodeling sequence in the rat.

A detailed chronological electron-microscopic study of the bone remodeling sequence has been performed in the rat based on a previously described model (Tran Van et al. 1982) in which the remodeling activity is synchronized. This allowed the observation of the cellular and extracellular events during the bone remodeling process, including the activation of the sequential process and the reversal phase, intermediate between osteoclastic resorption and osteoblastic formation. Most important is the fact that throughout the whole process cells with the morphological characteristics of mononuclear phagocytes have been observed in proximity or in contact with the bone surface and/or the various bone cells. Coated pits (receptor-mediated endocytosis) are frequently observed in close apposition ot bone spicules and gap junctions are frequent between the cells. These observations suggest that, besides being likely candidates as osteoclast precursors, mononuclear phagocytes may play an important role in bone remodeling.

The pathogenesis of infantile malignant osteopetrosis: Bone mineral metabolism and complications in five infants

Bone mineral metabolism was studied in five infants aged 8 to 22 months with severe osteopetrosis. There were findings consistent with biochemical osteomalacia. These included hypocalcemia, hypophosphatemia, high serum acid phosphatase and alkaline phosphatase activity, high levels of serum parathyroid hormone, and high urinary cyclic AMP. Serum 1,25(OH) 2 vitamin D 3 level was high in the one patient tested. Radiographs in all infants revealed rachitic changes in the metaphyses. However, dense bones on radiographs, calcium balance studies, and radiocalcium absorption studies demonstrated markedly positive calcium balance. Iliac crest bone biopsies showed increased quantity of woven bone with abundant numbers of osteoclasts, excessive amounts of osteoid, myelofibrosis, and a decreased number of Howship's lacunae. The wide bands of unmineralized osteoid did not take up tetracycline. In vitro bone resorbing activity due to osteoclast activating factor from cultured stimulated leukocytes was normal. Bone turnover however, was low as evidenced by low urinary hydroxyproline levels. We interpret these findings as indicating there is decreased bone remodeling and resorption in spite of increased humoral stimuli and osteoclasts. Since calcitonin levels were normal for age, the most likely cause of the impaired bone remodeling sequence was defective osteoclast function. We postulate that there may be a common genetic defect in phagocyte cells, including monocytes, neutrophils, and osteoclasts, which accounts for the abnormalities of mineral metabolism and previously reported hematologic, neurologic, and infectious complications.