The role of macrophages during embryonic endochondralen ossification in wild-type and osteoclast deficient mice.

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During embryonic development the cartilage anlage of the skeletal element needs to be remodeled into bone, a process referred to as endochondral ossification. For this the hypertrophic chondrocytes need to be removed so that a bone marrow cavity can form. The mineralized matrix of fully maturated hypertrophic chondrocytes is left behind in this process and serves as a platform for perichondrium-derived osteoblast precursors that migrate in together with blood vessels to mature and to build the trabecular bone. The removal of hypertrophic chondrocytes probably requires the concerted action of different cells, such as endothelial cells, osteoclasts, chondroclasts and septoclasts as the lack of any one of the cell types alone does not result in a loss of bone marrow cavity formation. Nevertheless, the loss of some cell types such as the osteoclasts leads to changes in the cellular environment. As such mutants lacking factors required for osteoclast differentiation, e.g. c-fos or Rank receptor, are osteoclast-deficient, but have increased numbers of macrophages present in the bone marrow. In the past years macrophages got a lot of attention. They are very heterogenous, long-lived, and biosynthetically active cells that are classically known for their functions in inert and adaptive immune responses. They also play a role in morphogentic processes in development and tumorigenesis. Little is known about the role of macrophages in the bone marrow; they have been implicated in stimulating osteoblast activity and the maintenance of the hematopoietic niche. The macrophages in the bone marrow are like in other organs of dual origin, the resident macrophages are yolk sac derived and others are derived from the hematopoietic myloid lineage. In the proposed project, we want to perform a comparative analysis of long bone development in Rank mutant mice, which have about 3 times more macrophages than wild types, with Pu.1 deficent mice that lack macrophages all together. Preliminary data revealed growth plate alterations in Rank newborn mutants that are not observed in Pu.1 mutants at E18.5. We also want to adress the origin of the macrophage population that is increased in the Rank mutant and analyse whether their composition with regard to M1 or M2 populations is altered. In addition, as part of this proposed project we want to analyse the underlying mechanisms of growth plate alteration in the Rank mutant. Last but not least we want to examine the functional consequences on embryonic bone development and postnatal maintenance upon conditionally eliminating the yolk sac derived macrophage population using an inducible, conditional Cre/flox approach. All together we expect from these experiments new insights into the role of macrophages under normal and genetically altered conditions.