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In Eurasia, the period between 40,000 and 30,000 BP saw the replacement of Neandertals by anatomically modern humans (AMH) during and after the Middle to Upper Paleolithic transition. The human fossil record for this period is very poorly defined with no overlap between Neandertals and AMH on the basis of direct dates. Four new (14)C dates were obtained on the two adult Neandertals from Spy (Belgium). The results show that Neandertals survived to at least approximately 36,000 BP in Belgium and that the Spy fossils may be associated to the Lincombian-Ranisian-Jerzmanowician, a transitional techno-complex defined in northwest Europe and recognized in the Spy collections. The new data suggest that hypotheses other than Neandertal acculturation by AMH may be considered in this part of Europe.

R e s e a R c h a R t i c l e8under this pathological condition, we induced estrogen deficiency by bilateral ovariectomy (OvX) in 20-week-old WT and RXR-KO mice and assessed bone loss over a further 8 weeks. Consistent with the lack of a skeletal phenotype in RXR-KO females (Supplemental Figure 3), age-and sex-matched sham-operated WT and RXR-KO mice showed no differences in bone architecture or osteoclast activity ( Figure 2). However, after OvX, loss of trabecular bone mass was significantly lower in RXR-KO mice (Figure 2, A-D). In WT mice, OvX led to a marked increase in osteoclast activity, shown by a rise in urine DPD and plasma CTX concentrations (Figure 2, E and F). In contrast, the increase in DPD and CTX concentrations was significantly lower in ovariectomized RXR-KO mice (Figure 2, E and F). These findings indicate that the diminished osteoclast activity in RXR-KO female mice makes them less prone to bone loss upon OvX. Lack of RXRs leads to formation of giant and nonresorbing osteoclasts in vitro.To determine the mechanism underlying the abnormal osteoclast activation in RXR-KO mice, we cultured bone marrow cells in the presence of the cytokines macrophage colony-stimulating factor (M-CSF) and RANKL (16). Osteoclasts differentiated from RXR-KO bone marrow were significantly larger than WT-derived osteoclasts and contained more nuclei (Figure 3, A-C). In contrast, osteoclast differentiation from bone marrow cells lacking RXRα but not RXRβ was normal, supporting the functional redundancy of RXRα and RXRβ in hematopoietic cells (Supplemental Figure 5). Enlargement of osteoclasts can result in increased bone resorption (17); however, the abnormally large RXR-KO osteoclasts displayed low lytic activity when cultured in calcium-phosphate-coated plates (Figure 3D) or on bovine cortical bone slices ( Figure 3E). RXR-KO osteoclasts also showed low expression of Acp5, matrix metallopeptidase 9 (Mmp9), cathepsin-K (CtsK), and Car2, which encode molecules crucial for extracellular matrix degradation and bone resorption ( Figure 3F). In addition, real-time imaging showed that RXR-KO osteoclasts had an increased spreading over the substrate compared with WT osteoclasts ( Figure 3G and Supplemental Video 1). These in vitro results are consistent with our in vivo observations, indicating that the lack of RXRs in osteoclast progenitors leads to a cell-autonomous effect on osteoclast differentiation and activation.The M-CSF response is altered in RXR-KO osteoclast progenitors. Osteoclast size is determined by the response of osteoclast progenitors to M-CSF, which controls their proliferation and survival (18,19). This cytokine also stimulates activities of the mature resorptive osteoclast, such as spreading, motility, and cytoskeletal organization (20). We thus hypothesized that the RXR-KO osteoclast phenotype could be due to an altered M-CSF response. To test this, we first characterized the capacity of osteoclast progenitors to form myeloid colony-forming units (CFUs) and to divide in response to M-CSF. After 12 days...

Background. Hyperphosphataemia is a risk factor for arterial calcification contributing to the high cardiovascular mortality in patients with chronic kidney disease. Calciumbased phosphate binders can induce hypercalcaemia and are associated with progression of vascular calcification. Therefore, the effect of lanthanum carbonate, a non-calcium phosphate binder, on the development of vascular calcification was investigated in uraemic rats. Methods. Chronic renal failure (CRF) was induced by feeding rats an adenine-enriched diet for 4 weeks. After 2 weeks, 1% or 2% lanthanum carbonate was added to the diet for 6 weeks. Calcification in the aorta, carotid and femoral arteries was evaluated histomorphometrically, biochemically and by ex vivo micro-CT. Chondro-/osteogenic conversion of vascular smooth muscle cells was also analysed in the rat aorta. Results. Treatment with 1% lanthanum carbonate (1% La) did not reduce vascular calcification, but in the 2% lanthanum carbonate (2% La) group vascular calcium content and area% Von Kossa positivity were decreased compared with control CRF rats. The aortic calcified volume measured with ex vivo micro-CT was significantly reduced in rats treated with 2% La. Although calcification was inhibited by treatment with 2% La, the chondrocyte transcription factor sox-9 was abundantly expressed in the aorta. Conclusion. Treatment of CRF rats with 2% La reduces the development of vascular calcification by adequate phosphate binding resulting in a decreased supply of phosphate as a substrate for vascular calcification.

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