Mechanism Of Bone Destruction Research Articles

Bone matrix degradation by the plasminogen activation system. Possible mechanism of bone destruction in arthritis.

The observed increase in urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR) in synovial tissue of patients with rheumatoid arthritis (RA) suggests pathophysiological involvement of the plasminogen activation (PA) system in inflammatory joint disease. In the present study, we investigated the capacity of the PA system to degrade non-mineralized and mineralized bone-like matrix in vitro as a model for bone destruction. Transfected mouse LB6 cell lines, that expressed either human u-PA or u-PAR, were cultured separately and simultaneously on radiolabelled bone matrix in the presence of plasminogen. Osteoblast-like murine calvarial MC3T3-E1 cells were used to produce a well-characterized, highly organized bone-like matrix, that could be mineralized in the presence of beta-glycerol phosphate. Bone matrix degradation was followed by the release of radioactivity in the culture medium. u-PA-producing cells, in contrast to u-PAR-producing cells, degraded both non-mineralized and mineralized bone matrix. This effect could be inhibited by anti-u-PA antibodies, as well as by tranexamic acid and by aprotinin, indicating that the degrading activity is u-PA mediated and plasmin dependent. Co-cultivation of a small portion of u-PA-producing cells with u-PAR-expressing cells resulted in a marked increase in degradation activity. Reduction of this potentiating effect by suramin or the amino-terminal fragment of u-PA, both competitive inhibitors of u-PA receptor binding, shows that this synergistic effect is due to binding of u-PA to u-PAR. u-PAR must be cell associated, as binding of u-PA to a soluble u-PAR prevented this enhancement. The capability of the PA system to degrade bone matrix in vitro, and the previously demonstrated increased expression of u-PA and u-PAR in synovial tissue of patients with RA, further support a role for the PA system in the development of bone erosions.

Bone resorption by tartrate-resistant acid phosphatase-positive multinuclear cells isolated from rheumatoid synovium.

Inflammatory reactions in rheumatoid arthritis (RA) often cause severe joint destruction. However, the mechanism of bone destruction is still a matter of controversy. To determine whether multinuclear cells found in the rheumatoid synovium can resorb bone, isolated synovial cells were assessed for tartrate-resistant acid phosphatase (TRAP) staining and the ability to resorb bone in a dentine resorption assay. TRAP-positive multinuclear cells were found in six out of 10 samples. These six samples showed resorption pit formation on dentine slices. The other four samples did not form resorption pits. The results of this study demonstrate that TRAP-positive multinuclear cells isolated from the rheumatoid synovium form resorption pits on dentine slices. Our results suggest that inflamed synovial cells in rheumatoid joints might participate in bone destruction.

Mechanisms involved in the metastasis of cancer to bone.

The metastasis of cancer to bone is a frequent outcome of common malignancies and is often associated with significant morbidity due to osteolysis. Bone metastasis is also selective in that a disproportionately small number of malignancies account for the majority of tumors which spread to bone. While the mechanisms of bone destruction have been studied, those responsible for the site-specific nature of bone metastasis are poorly understood. As a metastatic target, bone is unique in that it is continuously being remodelled under the influence of local and systemic growth factors, many of which are embedded in the bone matrix. This review summarizes evidence for the hypothesis that the formation of metastatic tumors in bone is the consequence of a unique microenvironment where metastatic cells can alter the metabolism of bone, thereby regulating the release of soluble bone-derived growth factors as a consequence of bone resorption. These, in turn, can modulate the malignant phenotypic properties of receptive cells. Transforming growth factor-beta is one factor which can promote the growth and motility of Walker 256 cells, a rat cell line with a propensity to metastasize spontaneously to bone.

Disodium Pamidronate Identifies Differential Osteoclastic Bone Resorption in Metastatic Prostate Cancer

In a controlled trial the effects of the osteoclast inhibitor disodium pamidronate were studied over a 6-month period in men with metastatic bone disease from prostate cancer. Using serial biochemical measurement of metabolic bone activity, and complementary subjective and quantitative bone histology, the effects of pamidronate were evaluated in tumour-free and metastatic regions of the skeleton, enabling analysis of the differential mechanisms of bone destruction in this disease. Following treatment, abnormally high markers of bone breakdown fell significantly (fasting urine hydroxyproline/creatinine (OHP): P less than 0.05; fasting urine calcium excretion (CaE): P less than 0.0001), confirming that activated osteoclasts play an integral role in the osteolytic process. Serial histomorphometry of bone from tumour-free areas showed that pamidronate restored abnormal levels of bone erosion to normal in 93% of cases. Suppression of bone destruction was also evident within metastases, although this was incomplete. The results confirm that osteoclast overactivity is responsible for a significant proportion of the accelerated osteolysis seen in both tumour-free and infiltrated bone in patients with prostate cancer. The differential effects in tumour-free and infiltrated bone suggest that the mechanisms of osteoclast activation may differ in metastatic and non-metastatic regions of the skeleton.

An investigation of vanishing bone disease

Vanishing bone disease is a rare condition producing local deformity and instability. Fibrovascular tissue replaces bone completely but the mechanism of bone destruction and resorption is unknown and there is controversy regarding the presence or absence of osteoclasts in the disease. Radiography, clinical chemistry, light microscopy, transmission electron microscopy (TEM) and cytochemistry were used to investigate the condition of a young woman presenting early in the disease process. We detected atypical ultrastructure in osteoblasts and endothelial cells. The rare osteoclasts, numerous mononuclear phagocytes and vascular endothelium found in the condition reacted positively for the enzyme acid phosphatase. Aggressive local excision of diseased tissue and insertion of a free vascularized bone graft at an advanced stage of the disease, accompanied by subsequent radiotherapy for residual disease only were successful in rehabilitating the affected forearm and hand.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

Mechanism of bone destructiondue to middle ear cholesteatoma as revealed by laser-Raman spectrometry

In an investigation of the mechanism of bone destruction caused by chronic otitis media complicated with cholesteatoma, both the processes of demineralization and remineralization were studied in an animal model and clinically at the molecular level, using a laser-Raman spectrometer. From this investigation, it is proposed that the mechanism of bone destruction associated with cholesteatoma is a form of demineralization.

Bone destruction and hypercalcemia in plasma cell myeloma.

M YELOMA is almost always associated with a marked increase in destructive osteolytic bone lesions. Bone destruction in myeloma is responsible for the most distressing clinical features of this disease, including intractable bone pain, fractures occurring either spontaneously or following trivial injury, and hypercalcemia with its attendant symptoms and signs. Eighty percent of patients present with bone pain as a predominant symptom.’ The bone lesions occur in several patterns. Occasionally, patients develop single osteolytic lesions that are associated with solitary plasmacytomas. Some patients have diffuse osteopenia, which mimics the appearance of osteoporosis, and is due to the myeloma cells being spread diffusely throughout the axial skeleton. In most patients there are multiple discrete lytic lesions occurring at the site of deposits or nests of myeloma cells. Bone scans in myeloma show very little abnormality. Isotopic bone scans are performed with labeled bisphosphonates that are taken up at sites of mineral deposition and reflect increased activity of bone forming cells. Myeloma is characterized by discrete lytic lesions with little increase in formation and this is probably the explanation for the difference in appearance between the bone scan in myeloma and the bone scan in breast cancer, where osteoblast activity is frequently increased. Similarly, serum alkaline phosphatase, which also reflects osteoblast activity, is usually not increased in patients with myeloma, unless they have coexistent pathological fractures. Most available evidence suggests that the mechanism of bone destruction in myeloma is primarily osteoclastic. This was first suggested in a study in which morphologic examination was performed on autopsy and biopsy samples of bone from a series of 37 patients with myeloma.’ In this series, active osteoclastic bone resorption was found predominantly in specimens that contained more than 20% marrow myeloma cell infiltration. In specimens of bone from myeloma patients that contained few or no myeloma cells, little osteoclast activity or evidence of active bone resorption was observed. This suggested that the myeloma cells caused the osteoclast activity that led to increased bone resorption. The association between increased osteoclasts on bone resorbing surfaces and areas of heavy myeloma cell infiltration was confirmed in a later study using the technique of quantitative bone histomorphometry on undecalcified transiliac bone biopsies from 118 patients with myeloma.3 Surprisingly, no decrease in mean trabecular bone volume was observed, but abnormalities were observed in bone formation. Bone forming surfaces were increased away from the areas of heavy myeloma cell infiltration but the osteoid seams were reduced in thickness and had a lowered calcification rate. The authors suggested that the activity of individual osteoblasts may be reduced in many patients with myeloma, accounting for these latter findings. Further evidence that the mechanism of bone resorption in myeloma is primarily osteoclastic is provided by data that show drugs that are specific inhibitors of osteoclast activity such as the bisphosphonates, mithramycin, and corticosteroids are usually very effective in lowering the serum calcium in patients with myeloma.4,“16 Not all workers have found increased osteoelastic resorption in myeloma. Schechter et al’ saw little evidence of osteoclastic activity in the patients they studied. MacDonald et al” suggested that murine myeloma cells had the capacity to destroy bone directly in vitro independent of osteoclasts, in a similar manner described earlier for human breast cancer cells.’ Whether this phenomenon has an in vivo significance is not currently known, In some patients with myeloma, osteosclerosis

Histomorphometric analysis of osteoclastic bone resorption in metastatic bone disease from various primary malignomas.

The present study deals with qualitative und quantitative analysis of osteoclastic bone resorption in metastatic bone disease. 267 cases were examined histomorphologically and divided into three developmental stages. In the first 'phase of early appearance' no bone resorption takes place. The stimulation of osteoclastic resorption in the surroundings of tumour tissue is typical in the second 'phase of interaction'. Pressure atrophy, aseptic necrosis and osteolysis by the tumour cells themselves are other mechanisms of bone destruction in the last 'phase of carcinomatosis'. Because osteoclasts are exclusively responsible for the loss of bone tissue in the 'phase of interaction', this stage is suited for precise quantitative analysis of osteoclastic resorption. 24 pure osteolytic secondary bone tumours of various primary lesions were examined histomorphometrically. The numerical values were compared with each other and with standard values of healthy individuals. In contrast with normal bone tissue the fractional resorption surfaces und osteoclast indices increase in metastases. Activated osteoclasts are larger and have more nuclei. The numbers of osteoclast index and nuclei per osteoclast are significantly higher in renal than in breast carcinoma. Osteoclasts can be activated in distances of more than 500 micron from tumour tissue. The mean stimulation distance in metastasis from squamous cell carcinoma is markedly higher than in secondary bone tumours of breast carcinoma. Several osteoclast activating substances and divers mechanisms of stimulation might be responsible for different numerical values of morphometric parameters in metastases from various primary malignancies.

Further observations on mechanisms of bone destruction by squamous carcinomas of the head and neck: The role of host stroma

Further observations on mechanisms of bone destruction by squamous carcinomas of the head and neck: The role of host stroma

A histometric study of the effect of indomethacin and calcitonin on bone remodelling in hamster periodontitis

The action on bone remodelling of indomethacin, a potent inhibitor of prostaglandin (PG) synthesis, was determined in hamster periodontitis and compared to that of calcitonin. The two treatments reduced the extent of bone resorption considerably but not significantly (NS). The reversal phase, the intermediate step between resorption and formation, was decreased by 33 per cent (NS) by indomethacin and 75 per cent by calcitonin ( p < 0.02). Bone formation was increased by 270 per cent with indomethacin ( p < 0.05) and by 400 per cent with calcitonin ( p < 0.03), compared with untreated animals. This exceeded the extent of bone formation activity in control animals. These data strongly suggest that PG are involved in the mechanism of bone destruction in hamster periodontitis and that PG are potent in vivo uncouplers of bone remodelling as they participate both in an increase in bone resorption and a decrease in bone formation. A partial decrease in reversal lacunae indicates that other factors, also acting as uncouplers, probably take part in the mechanism of bone destruction.

Further observations on mechanisms of bone destruction by squamous carcinomas of the head and neck: the role of host stroma.

Mechanisms of bone invasion by squamous carcinomas of the head and neck have been investigated using fresh tumours and established tumour cell lines in an in vitro bone resorption assay with 45Ca-labelled mouse calvaria. Fresh tumours regularly resorb bone in vitro. Activity is consistently reduced by indomethacin. The tumours release E2 prostaglandins (PGE2) in amounts sufficient to account for approximately 50% of the bone resorption observed. Small amounts of non-prostaglandin (indomethacin-resistant) osteolytic factors are also produced. Control non-neoplastic tissues show a variable capacity to resorb bone in vitro; PGE2 levels in these tissues may be related to their content of inflammatory cells. Tumour cell lines also resorb bone in vitro but, for most lines, activity is not significantly blocked by indomethacin and PGE2 levels are generally insufficient to account for the osteolysis observed. Non-prostaglandin bone resorbing factors thus predominate. It is concluded that most squamous cancers of the head and neck are osteolytic in vitro and release a mixture of prostaglandin and non-prostaglandin factors which stimulate osteoclastic bone resorption. These factors are derived from both neoplastic and stromal elements, and are "tumour-associated" rather than "tumour-specific". In vitro bone resorption and prostaglandin release does not correlate with pathological features of the tumour or with post-operative survival.

Mechanisms of bone destruction in the development of skeletal metastases.

SKELETAL metastases are associated with progressive bone destruction but the pathogenesis is not well understood. I report here experiments which indicate that two principal mechanisms are involved. The first is mediated by osteoclasts and the tumour secretes a diffusable osteoclast activating factor; the second functions when the residual trabeculae are surrounded by the tumour cells.