Lymphocytes and the Dap12 Adaptor Are Key Regulators of Osteoclast Activation Associated with Gonadal Failure

Bone resorption by osteoclasts is necessary to maintain bone homeostasis. Osteoclast differentiation from hematopoietic progenitors and their activation depend on M-CSF and RANKL, but also requires co-stimulatory signals acting through receptors associated with DAP12 and FcRγ adaptors. Dap12 mutant mice (KΔ75) are osteopetrotic due to inactive osteoclasts but, surprisingly, these mice are more sensitive than WT mice to bone loss following an ovariectomy. Because estrogen withdrawal is known to disturb bone mass, at least in part, through lymphocyte interaction, we looked at the role of mature lymphocytes on osteoclastogenesis and bone mass in the absence of functional DAP12. Lymphocytes were found to stimulate an early osteoclast differentiation response from Dap12-deficient progenitors in vitro. In vivo, Rag1-/- mice lacking mature lymphocytes did not exhibit any bone phenotype, but lost their bone mass after ovariectomy like KΔ75 mice. KΔ75;Rag1-/- double mutant female mice exhibited a more severe osteopetrosis than Dap12-deficient animals but lost their bone mass after ovariectomy, like single mutants. These results suggest that both DAP12 and mature lymphocytes act synergistically to maintain bone mass under physiological conditions, while playing similar but not synergistic co-stimulatory roles in protecting bone loss after gonadal failure. Thus, our data support a role for lymphocytes during osteoclast differentiation and suggest that they may function as accessory cells when regular osteoclast function is compromised

Influence of periphyton substrates and rearing density on Liza aurata growth and production in marine nursery ponds

The main objectives of this investigation were to test the effects of (i) the presence of periphyton substrates, (ii) rearing density and (iii) supplemental feeding with dry feed on the growth and production of golden mullet (Liza aurata) juveniles. Twenty-six 1 m2-cages were installed in a French marine pond from April till June 2008. Mullets were stocked in cages with or without substrate at a density of 0, 20, 40 or 60 individuals per cage. Each treatment was carried out in triplicate. In addition, 20 fish were put in three tanks and fed ad libitum with dry feed. The results showed that (i) although mullets were seen to graze on periphyton substrates, their presence did not affect mullet growth and production. In future studies, meshed substrates could be attached on hard structures to improve the efficiency of mullet grazing; (ii) individual growth was higher at low density due to a lower competition for space and food. Production increased with rearing density reflecting that food availability was not limiting in control cages; (iii) growth and net yield of mullets were lower in fed tanks than in natural ponds where food seemed to be more appropriate for wild mullet juveniles and where stress factors were lower. Finally, in contrast to the individual growth rate, the net fish yield in this experiment was greater than that recorded in other extensive and semi-intensive systems. It was equivalent to yields observed in other periphyton-based systems. Periphyton developed on the meshed walls of cages probably increased the natural productivity of the pond. As part of sustainable aquaculture development, the effluents of intensive farms could be exploited to produce periphyton on inflexible substrates and to rear mullet adults, which are more herbivorous than juveniles. This type of integrated system could be developed with other mullet species, such as Chelon labrosus or Mugil cephalus, whose growth rates are higher than L. aurata. Mullet production could be exploited by the sale of fillets and dried ro

Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages

International audienc

Spinal cord injury reprograms muscle fibro-adipogenic progenitors to form heterotopic bones within muscles

AbstractThe cells-of-origin of neurogenic heterotopic ossifications (NHO), which develop frequently in the periarticular muscles following spinal cord injuries (SCI) and traumatic brain injuries, remain unclear because the skeletal muscle harbors two progenitor cell populations: satellite cells (SCs) which are myogenic, and fibro-adipogenic progenitors (FAPs) which are mesenchymal. Lineage-tracing experiments using the Cre recombinase /LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen specifically expressed in either SCs or FAPs in the skeletal muscles under the control of the Pax7 or Prrx1 gene promotors respectively. These experiments demonstrate that following a muscle injury, SCI causes the upregulation of PDGFRα on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with instead reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHO. No cells expressing ZsGreen under the Prrx1 promoter were detected in the blood after injury suggesting that the cells-of-origin of NHO are locally derived from the injured muscle. We validated these findings in the human pathology using human NHO biopsies. PDGFRα+ mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice whereas CD56+ myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to uncontrolled proliferation and differentiation into osteoblasts.</jats:p

Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles

AbstractThe cells of origin of neurogenic heterotopic ossifications (NHOs), which develop frequently in the periarticular muscles following spinal cord injuries (SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells (SCs), which are myogenic, and fibroadipogenic progenitors (FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing ZsGreen under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+ mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+ myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.</jats:p

Osteoclast activity modulates B-cell development in the bone marrow

B-cell development is dependent on the interactions between B-cell precursors and bone marrow stromal cells, but the role of osteoclasts (OCLs) in this process remains unknown. B lymphocytopenia is a characteristic of osteopetrosis, suggesting a modulation of B lymphopoiesis by OCL activity. To address this question, we first rescued OCL function in osteopetrotic oc/oc mice by dendritic cell transfer, leading to a restoration of both bone phenotype and B-cell development. To further explore the link between OCL activity and B lymphopoiesis, we induced osteopetrosis in normal mice by injections of zoledronic acid (ZA), an inhibitor of bone resorption. B-cell number decreased specifically in the bone marrow of ZA-treated mice. ZA did not directly affect B-cell differentiation, proliferation and apoptosis, but induced a decrease in the expression of CXCL12 and IL-7 by stromal cells, associated with reduced osteoblastic engagement. Equivalent low osteoblastic engagement in oc/oc mice confirmed that it resulted from the reduced OCL activity rather than from a direct effect of ZA on osteoblasts. These dramatic alterations of the bone microenvironment were disadvantageous for B lymphopoiesis, leading to retention of B-cell progenitors outside of their bone marrow niches in the ZA-induced osteopetrotic model. Altogether, our data revealed that OCLs modulate B-cell development in the bone marrow by controlling the bone microenvironment and the fate of osteoblasts. They provide novel basis for the regulation of the retention of B cells in their niche by OCL activity