The Increased Bone Mass in ΔFosB Transgenic Mice Is Independent of Circulating Leptin Levels

Abstract

Transgenic mice overexpressing deltaFosB, a naturally occurring splice variant of FosB, develop an osteosclerotic phenotype. The increased bone formation has been shown to be due, at least in part, to autonomous effects of deltaFosB isoforms on cells of the osteoblast lineage. However, abdominal fat and marrow adipocytes are also markedly decreased in deltaFosB mice, leading to low serum leptin levels. Increased bone mass has been linked to the absence of leptin and leptin receptor signaling in ob/ob and db/db mice. Thus, in addition to affecting directly osteoblastogenesis and bone formation, deltaFosB isoforms might increase bone mass indirectly via a decrease in leptin. To test this hypothesis, we restored normal circulating levels of leptin in deltaFosB mice via sc implanted osmotic pumps. Complete histomorphometric analysis demonstrated that trabecular bone volume as well as dynamic parameters of bone formation was unchanged by this treatment in both deltaFosB transgenic mice and control littermates. This demonstration that restoring circulating levels of leptin in deltaFosB transgenic mice failed to rescue the bone phenotype further indicates that the marked increase in bone formation is autonomous to the osteoblast lineage.

ΔFosB Induces Osteosclerosis and Decreases Adipogenesis by Two Independent Cell-Autonomous Mechanisms

“…We had previously found, however, that marrow cells from the NSE-⌬FosB mice formed markedly fewer adipocytes in culture than did those from control animals (47). When bone marrow stromal cells from control, OG2-⌬FosB, and NSE-⌬FosB mice were cultured with ascorbic acid and ␤-glycerophosphate, the adipogenic capacity of bone marrow cultures from OG2-⌬FosB transgenic mice, shown by staining with Oil Red O, was comparable to that of cultures established from control mice, while adipocyte formation was dramatically reduced in cultures from NSE-⌬FosB transgenic mice, as reported previously (25,47) (Fig. 3C).…”

“…In vivo, an inverse relationship between the number of osteoblasts and bone marrow adipocytes has been demonstrated in several forms of osteopenia, where decreased bone mass is often associated with increased adipogenesis (6,29,57,60). Conversely, we have reported an osteosclerotic phenotype accompanied by decreased adipogenesis in transgenic mice that overexpress the AP-1 transcription factor ⌬FosB under the control of the NSE promoter (25,47,53).…”

“…We have recently reported that transgenic mice overexpressing ⌬FosB, a member of the activator protein 1 (AP-1) family of transcription factors, under the control of the neuron-specific enolase (NSE) promoter develop not only a severe and progressive osteosclerotic phenotype, characterized as increased bone formation, but also a pronounced decrease in adipogenesis and fat levels (25,47,53). The AP-1 family of basic leucine zipper transcription factors comprises various combinations of Jun (c-Jun, JunB, and JunD) and Fos (c-Fos, FosB, Fra-1, and Fra-2) proteins, which upon dimer formation regulate gene transcription by binding to consensus response elements present in the promoter region of target genes (23).…”

Elevated Fra-1 expression causes severe lipodystrophy

“…As expected from reduced fat storage, Fra1tg mice show a reduced level of circulating leptin that might contribute to increased bone formation by osteoblasts (Ducy et al, 2000). However, this decreased level of leptin was not sufficient to affect the food intake of the Fra1tg mice, and although the role of leptin in regulating bone mass can be dissociated from its function in regulating appetite (Shi et al, 2008), leptin was not found to have a role in the very similar bone phenotype that developed in DfosB transgenic mice (Kveiborg et al, 2002). Osteocalcin was recently characterized as a hormone that regulates insulin production by increasing -cell proliferation (Lee et al, 2007).…”

Osteoblast-specific expression of Fra-2/AP-1 controls Adiponectin/Osteocalcin expression and affects metabolism

“…In mice loss-and gain-of-function mutations of Fos and ATF members, and to a lesser extent of Jun members, demonstrate that these factors are important for osteoblast differentiation and function (Wagner and Eferl, 2005). Whereas Fra-1 (Fos-related antigen 1, Fosl1) and DFosB (the short isoform of FosB) promote osteoblast differentiation and activity Kveiborg et al, 2002;Lefterova and Lazar, 2009;Zhao et al, 2008), Fra-2 (Fosrelated antigen 2, Fosl2) is important in normal physiology and disease, such as in pulmonary fibrosis . Fra-2 also regulates chondrocyte differentiation and bone remodeling by controlling osteoclast size and activity (Bozec et al, 2008).…”