A new function of Nell-1 protein in repressing adipogenic differentiation

Abstract

A theoretical inverse relationship has long been postulated for osteogenic and adipogenic differentiation (bone versus adipose tissue differentiation). This inverse relationship in theory at least partially underlies the clinical entity of osteoporosis, in which marrow mesenchymal stem cells (MSCs) have a predilection for adipose differentiation that increases with age. In the present study, we assayed the potential anti-adipogenic effects of Nell-1 protein (an osteoinductive molecule). Using 3T3-L1 (a human preadipocyte cell line) cells and human adipose-derived stromal cells (ASCs), we observed that adenoviral delivered (Ad)-Nell-1 or recombinant NELL-1 protein significantly reduced adipose differentiation across all markers examined (Oil red O staining, adipogenic gene expression [Pparg, Lpl, Ap2]). In a prospective fashion, Hedgehog signaling was assayed as potentially downstream of Nell-1 signaling in regulating osteogenic over adipogenic differentiation. In comparison to Ad-LacZ control, Ad-Nell-1 increased expression of hedgehog signaling markers (Ihh, Gli1, Ptc1). These studies suggest that Nell-1 is a potent anti-adipogenic agent. Moreover, Nell-1 signaling may inhibit adipogenic differentiation via a Hedgehog dependent mechanism.

Human Perivascular Stem Cells Show Enhanced Osteogenesis and Vasculogenesis with Nel-Like Molecule I Protein

“…1E). Consistent with published reports in other cell types, 28,32 hPSCs treated with NELL-1 protein (300 ng/mL) showed an increase in both ALP and AR staining at 5 and 10 days of osteogenic differentiation, respectively (Fig. 1D, E).…”

“…19,28,* In the current study we directly compared the effect so BMP-2 and NELL-1 in PSC-mediated ectopic bone formation. Significantly, different qualities in bone regenerate were found: while BMP-2 induced a higher density of bone, this was also intermixed with lipid accumulation.…”

“…26,27 The medium was supplemented with 300-600 ng/mL of NELL-1, as previously described. 28 Osteogenic differentiation was assessed using alkaline phosphatase (ALP) and alizarin red (AR) staining at 5 and 10 days of osteogenic differentiation, respectively (with or without 300 ng/mL NELL-1). The representative 38.4 · ALP and AR staining (n = 3) images were semiquantitatively analyzed using the magic wand tool of Adobe Photoshop CS5.…”

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

“…80 Because canonical Wnt inhibitors did not completely eliminate the antiadipogenic effect of NELL-1 on BMP2-induced adipogenesis, we hypothesize that other pathways, such as Hedgehog signaling, may be involved in adipogenic regulation. 81 The ability of NELL-1 to activate Wnt signaling suggests potential utility in conditions such as osteoporosis, in which the balance between osteogenesis versus adipogenesis and the balance between bone deposition versus resorption are perturbed to favor bone loss.…”

Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration

“…NELL-1 has been reported to induce robust osseous healing of critical-sized rat femoral segmental and calvarial defects [17,25,26], and also to promote lumbar spinal fusion in rats, sheep [21][22][23], and non-human primates. Additionally, NELL-1 has been identified not only to demonstrate anti-osteoclastic effects both in vitro and in vivo [19], but also to suppress adipogenesis [27]. Recently, a genomewide linkage study identified NELL-1 polymorphisms in patients with reduced bone mineral density [28], thus describing an association between NELL-1 and osteoporosis.…”