Sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity, is caused by loss of the SOST gene product, sclerostin. The localization in bone and the mechanism of action of sclerostin are not yet known, but it has been hypothesized that it may act as a bone morphogenetic protein (BMP) antagonist. We show here that SOST/sclerostin is expressed exclusively by osteocytes in mouse and human bone and inhibits the differentiation and mineralization of murine preosteoblastic cells (KS483). Although sclerostin shares some of the actions of the BMP antagonist noggin, we show here that it also has actions distinctly different from it. In contrast to noggin, sclerostin did not inhibit basal alkaline phosphatase (ALP) activity in KS483 cells, nor did it antagonize BMP-stimulated ALP activity in mouse C2C12 cells. In addition, sclerostin had no effect on BMP-stimulated Smad phosphorylation and direct transcriptional activation of MSX-2 and BMP response element reporter constructs in KS483 cells. Its unique localization and action on osteoblasts suggest that sclerostin may be the previously proposed osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation.

While quantitative studies reported especially disturbed emotional functioning, qualitative studies reported problems in all domains of child functioning. Well-designed studies are needed to gain more insight into the psychosocial functioning of children of cancer patients in order to develop tailored care.

Sclerostin is an osteocyte-derived negative regulator of bone formation. It inhibits BMPstimulated bone formation both in vitro and in vivo but has no direct effect on BMP signaling. Instead, sclerostin inhibits Wnt signaling that is required for BMP-stimulated osteoblastic differentiation.Introduction: Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize BMP activity. Sclerostin has been shown to inhibit BMP-stimulated bone formation, but its mechanism of action seems to be different from classical BMP antagonists. In this study, we investigated the mechanism by which sclerostin inhibits BMP-stimulated bone formation. Materials and Methods: DNA electroporation of calf muscle of mice using expression plasmids for BMP and sclerostin was used to study the effect of sclerostin on BMP-induced bone formation in vivo. Transcriptional profiling using microarrays of osteoblastic cells treated with BMP in the absence or presence of sclerostin was used to find specific growth factor signaling pathways affected by sclerostin. The affected pathways were further studied using growth factor-specific reporter constructs. Results: BMP-induced ectopic bone formation in calf muscle of mice was prevented by co-expression of sclerostin in vivo. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways. Sclerostin, however, did not inhibit stimulation of direct BMP target genes. Furthermore, we did not obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP-specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMPand Wnt-induced Wnt reporter construct activation. Conclusions: Sclerostin inhibits BMP-stimulated bone formation but does not affect BMP signaling. Instead, it antagonizes Wnt signaling in osteoblastic cells. High bone mass in sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling.

This study investigates emotional and behavioural problems in children of parents diagnosed with cancer and examines the relationship with demographic and illness-related variables. Furthermore, agreement and differences between informants regarding child's functioning were examined. Members of 186 families in which a parent had been diagnosed with cancer participated. More emotional problems were reported for latency-aged sons (ill parents) and adolescent daughters (ill parents; self-reports), whereas also better functioning was reported in adolescent children (spouses), compared to the norm group. Age and gender-effects were found: latency-aged sons were perceived as having more emotional problems than adolescent sons (ill parents); adolescent daughters as having more emotional and behavioural problems than adolescent sons (ill parents; self-reports). Results indicated a higher prevalence of problems when the father was ill than when the mother was (spouses and self-reports). The treatment intensity affected adolescent daughter's functioning (spouses), whereas adolescent son's functioning was affected by relapsed disease (self-reports). Adolescents and mothers perceived comparable levels of problems, but fathers perceived problems in children to be less prevalent. Findings suggest that adolescent daughters and latency-aged sons are at risk for emotional problems following the diagnosis of cancer in a parent. The perception of child's functioning and potential influencing variables varied according to informant.

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