A case of chondromatosis indicates a synovial stem cell aetiology.

OBJECTIVE: To evaluate cell cultures derived from intrasynovial nodules from a patient with primary synovial chondromatosis (PSC) for aberrant numbers/differentiation of osteochondroprogenitor cells. METHODS: Cell cultures were established from PSC synovial nodules, or normal bovine or human osteoarthritis (OA) synovia (for comparison). Multi-lineage potential was determined using well-characterized in vitro culture systems to assess osteogenic, chondrogenic and adipogenic capability. RESULTS: Primary PSC cell cultures were typically fibroblastic but contained islands of dense cell clusters/nodules, some of which were isolated and cultured separately [putative osteochondroprogenitris (pOCP) cultures]. OA synovial cultures had barely detectable levels of alkaline phosphatase (AP) that increased (0.006+/-0.008 to 0.141+/-0.000 nmol p-nitrophenol/min/cm(2)) with dexamethasone treatment. AP activity was higher in primary PSC cell cultures and further enhanced by dexamethasone (from 0.076+/-0.022 to 5.735+/-0.000 nmol p-nitrophenol/min/cm(2)). Histochemically, AP was localized as discreet areas within PSC cultures. No AP activity was detected histochemically in OA or normal bovine synovial cultures. The pOCP cultures had high basal AP (5.036+/-0.439 nmol p-nitrophenol/min/cm(2)) and spontaneously formed mineralized nodules, which increased in number under standard osteogenic conditions. Under chondrogenic conditions, micromass or pellet-cultured pOCP cells spontaneously synthesized a matrix containing glycosaminoglycans and collagen II. In adipogenic medium, the number of lipid-containing cells was increased. CONCLUSIONS: Compared with cultures established from OA or normal synovia, cell cultures established from PSC synovial nodules were enriched in osteochondroprogenitors, which, unlike normal mesenchymal cells, differentiated along chondrogenic and osteogenic lineages in the absence of dexamethasone.

Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables.

BACKGROUND: Receptor activator of nuclear factor kappabeta ligand (RANKL) has an important role in bone remodelling, and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) can induce apoptosis in cancer cells. Their functions are linked by their interactions with osteoprotegerin (OPG). OBJECTIVE: To investigate the expression of RANKL and TRAIL in a large series of unselected breast cancers and to analyse the relations between these expressions and the expression of OPG, oestrogen receptor, and clinicopathological variables. METHODS: 395 breast cancers were sampled into tissue microarrays and immunohistochemistry undertaken for RANKL and TRAIL. RESULTS: There was strong expression of RANKL in 14% of the cancers and strong expression of TRAIL in 30%. Expression of RANKL had a negative association with expression of oestrogen receptor (p = 0.036). Expression of TRAIL had a negative association with the Nottingham Prognostic Index (p = 0.021). There was a significant negative relation between expression of RANKL and TRAIL (p<0.005). Unsupervised cluster analysis produced a dendrogram that showed a clear division into two groups, and the expression of oestrogen receptor was significantly higher in one of those groups (p = 0.012). CONCLUSIONS: There is apparent loss of expression of RANKL in 86% of breast cancers; those tumours that retain expression tend to be oestrogen receptor negative and of a high histological grade. There is strong expression of TRAIL in 30% of breast cancers and these tend to be of better prognostic type. These results may be important in the processes of metastasis to bone and the apoptotic cell death pathway in cancer.

Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin.

Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFkappaB (RANKL). RANKL acting via its receptor, receptor activator of NFkappaB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo.

The potent bisphosphonate ibandronate does not induce myeloma cell apoptosis in a murine model of established multiple myeloma.

Bisphosphonates are effective in the management of bone disease in patients with multiple myeloma and recent reports have suggested that they may also have an anti-tumour activity. In support of this, we have previously demonstrated that bisphosphonates can induce myeloma cell apoptosis in vitro; however, it remains unclear whether this occurs in vivo. We have therefore investigated the effect of the potent bisphosphonate ibandronate in the 5T2MM murine model of established multiple myeloma. Short-term treatment with a high dose of ibandronate had no effect on either myeloma cell number or the proportion of myeloma cells undergoing apoptosis. These observations suggest that although bisphosphonates induce apoptosis in myeloma cells in vitro, they may not have the same anti-tumour effects in vivo.

Trihalomethanes as initiators and promoters of carcinogenesis.

Chloroform and other trihalomethanes are contaminants of drinking water that have been demonstrated to be carcinogenic in laboratory animals. Determination of the mechanism of carcinogenicity of chloroform is required so that the animal data can be extrapolated to estimate the human health hazard. The extent of the binding of chloroform to rat liver and kidney DNA was approximately 0.1% the level of binding found for dimethylnitrosamine. Neither chloroform nor bromoform, in contrast to diethylnitrosamine-initiated GGTase-positive foci in either intact or partial hepatectomized rats, promoted with phenobarbital. Tumor-promoting activity of chloroform was indicated by the slight significant increase, compared to untreated controls, in the incidence of GGTase-positive foci in rats initiated with diethylnitrosamine (DENA) followed by the administration of chloroform twice weekly for a total of 15 doses. In this study, rats administered only the DENA or the chloroform did not contain an increased incidence of GGTase-positive foci compared to untreated controls. However, the incidence of foci in the group that received DENA followed by chloroform was not statistically different from that in either the group that received only the DENA or only the chloroform. In conclusion, we were unable to demonstrate tumor-initiating activity for chloroform, and the tumor-promoting activity of chloroform indicated by our results requires further confirmation.