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The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.Leukemia ( Keywords: multiple myeloma; osteocytes; bone disease; osteoclasts INTRODUCTIONThe presence of osteolytic bone lesions or osteoporosis is the hallmark of multiple myeloma (MM), and leads to bone fragility and fractures in MM patients. The bone lesions are characterized by severely unbalanced and uncoupled bone remodelling in the area of plasma cell infiltration due to increased osteoclast (OCL) formation and activity, and osteoblast (OB) suppression. 1 --3 Local factors produced by MM cells and the bone marrow microenvironment are involved in the MM-induced increase in osteoclastogenesis, and include an imbalance in the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio that favours RANKL, 2,4 and the MM cell production of osteoclastogenic factors such as Chemokine (C --C motif) ligand 3 (CCL3)/macrophage inflammatory proteins (MIP)-1a. 5 --7 OB exhaustion is mainly due to a reduction in OB differentiation and formation, from mesenchymal stem cells and OB progenitors, that is induced by MM cells as a result of cell-to-cell contacts and the release of soluble factors. 3,8 --11 Osteocytes are differentiated cells of osteogenic lineage 12 located in the lacuno-canalicular system of the bone (see the review by Bonewald). 13 There is increasing evidence that they regulate physiological local bone remodelling, 13 --16 partly as a result of the cell death and apoptosis that triggers OCL formation and bone resorption, 15 --19 and partly by secreting sclerostin, a molecule that is specifically produced by osteocytes that inhibits bone formation. 20,21 Interestingly, an apoptosis-related reduction in osteocyte viability has recently been demonstrated in

The morphological changes undergone by the osteoblast at the ultrastructural level, during its differentiation into osteocyte, were studied in the primary parallel-fibred bone of the newborn rabbit by means of incomplete three-dimensional reconstruction from partially serial-sectioned preosteocytes. The findings obtained suggest that the formation of osteocyte cytoplasmic processes is an asynchronous and asymmetrical phenomenon that seems to precede the mineralization of the organic matrix and to give rise to an asymmetrical mature osteocyte. The functions of cytoplasmic processes as regards bone formation, cell nutrition and osteoblast modulation are discussed. The mechanism by which the osteoblast ‘enters’ the bone matrix is hypothesized.

The onset and development of intramembranous ossification centers in the cranial vault and around the shaft of long bones in five newborn rabbits and six chick embryos were studied by light (LM) and transmission electron microscopy (TEM). Two subsequent different types of bone formation were observed. We respectively named them static and dynamic osteogenesis, because the former is characterized by pluristratified cords of unexpectedly stationary osteoblasts, which differentiate at a fairly constant distance (28+/-0.4 microm) from the blood capillaries, and the latter by the well-known typical monostratified laminae of movable osteoblasts. No significant structural and ultrastructural differences were found between stationary and movable osteoblasts, all being polarized secretory cells joined by gap junctions. However, unlike in typical movable osteoblastic laminae, stationary osteoblasts inside the cords are irregularly arranged, variously polarized and transform into osteocytes, clustered within confluent lacunae, in the same place where they differentiate. Static osteogenesis is devoted to the building of the first trabecular bony framework having, with respect to the subsequent bone apposition by typical movable osteoblasts, the same supporting function as calcified trabeculae in endochondral ossification. In conclusion, it appears that while static osteogenesis increases the bone external size, dynamic osteogenesis is mainly involved in bone compaction, i.e., in filling primary haversian spaces with primary osteons.