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

Abstract

Site-specific adipose content of the bone marrow has been noted since the inclusion of meat into the hominid diet, evidenced by marrow removal from ungulate limb bones, 2.6 million years ago. Association between marrow fat and bone metabolism has since been documented, however the mechanism for this relationship remains unknown. Leptin, a secreted adipocytokine, possesses the ability to regulate bone formation centrally through the hypothalamus and peripherally though marrow cells such as the osteoblast. Until the recent generation of a mouse with loxP sites flanking exon17 of the signaling-competent leptin receptor (ObRb), the physiologic contribution of peripheral leptin signaling to bone formation could not be determined. Leptin has been shown to increase mineralization of primary bone marrow stromal precursor cells (MPCs) and osteoblasts in vitro. Leptin is also a potent regulator of pro-inflammatory macrophage cytokine output. We therefore examined the ability of leptin to modulate bone formation through the myeloid lineage, the osteoblast, and the MPC by generating mice with conditional deletion of ObRb using LysozymeM 2 (LysM), Col2.3, and Col3.6 promoters driving Cre recombinase respectively. Myeloid-specific deletion of ObRb resulted in a mild, gender-specific bone phenotype in 52 week old animals with decreases in trabecular parameters noted in females and increases in cortical values in males. This change mimics associations between circulating leptin and bone mineral density (BMD) observed in adult humans. Osteoblast ObRb deletion using Col2.3-Cre did not produce a discernable bone phenotype. However, conditional removal of ObRb with Col3.6-Cre on more primitive MPCs increased femoral length and trabecular and cortical femoral parameters at 12 and 52 weeks of age. Our results imply that at physiologic equilibrium, leptin regulation of mature osteoblast function is negligible, however, early modulation of MPCs may contribute to properties such as bone length and trabecular formation. In contrast, regulation of myeloid lineage cells such as macrophages may explain adult gender-specific differences in associations between circulating leptin and BMD. Further modulation of macrophage-associated leptin signaling by compounds such as amino-bisphosphonates may enhance the ability of leptin to contribute to bone formation as well as the pathogenesis of diseases such as osteonecrosis of the jaw.