Regulation of Bone Formation and Pathology by Local Actions of Leptin in the Bone Marrow.

[摘要] Site-specific adipose content of the bone marrow has been noted since the inclusionof meat into the hominid diet, evidenced by marrow removal from ungulate limbbones, 2.6 million years ago. Association between marrow fat and bone metabolismhas since been documented, however the mechanism for this relationship remainsunknown. Leptin, a secreted adipocytokine, possesses the ability to regulate boneformation centrally through the hypothalamus and peripherally though marrowcells such as the osteoblast. Until the recent generation of a mouse with loxP sitesflanking exon17 of the signaling-competent leptin receptor (ObRb), the physiologiccontribution of peripheral leptin signaling to bone formation could not be determined.Leptin has been shown to increase mineralization of primary bone marrow stromalprecursor cells (MPCs) and osteoblasts in vitro. Leptin is also a potent regulator ofpro-inflammatory macrophage cytokine output. We therefore examined the ability ofleptin to modulate bone formation through the myeloid lineage, the osteoblast, andthe MPC by generating mice with conditional deletion of ObRb using LysozymeM2(LysM), Col2.3, and Col3.6 promoters driving Cre recombinase respectively.Myeloid-specific deletion of ObRb resulted in a mild, gender-specific bonephenotype in 52 week old animals with decreases in trabecular parameters noted infemales and increases in cortical values in males. This change mimics associationsbetween circulating leptin and bone mineral density (BMD) observed in adulthumans. Osteoblast ObRb deletion using Col2.3-Cre did not produce a discernablebone phenotype. However, conditional removal of ObRb with Col3.6-Cre on moreprimitive MPCs increased femoral length and trabecular and cortical femoralparameters at 12 and 52 weeks of age. Our results imply that at physiologicequilibrium, leptin regulation of mature osteoblast function is negligible, however,early modulation of MPCs may contribute to properties such as bone length andtrabecular formation. In contrast, regulation of myeloid lineage cells such asmacrophages may explain adult gender-specific differences in associations betweencirculating leptin and BMD. Further modulation of macrophage-associated leptinsignaling by compounds such as amino-bisphosphonates may enhance the ability ofleptin to contribute to bone formation as well as the pathogenesis of diseases such asosteonecrosis of the jaw.

[发布机构] University of Michigan

[效力级别] Bone Metabolism

[关键词] Adipocytokine;Bone Metabolism;Endocrinology;Leptin;Bisphosphonate;Osteonecrosis of the Jaw;Biological Chemistry;Dentistry;Genetics;Molecular;Cellular and Developmental Biology;Science (General);Health Sciences;Science;Oral Health Sciences