Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Abstract

One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3␤ and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5 ؊/؊ , SAMP6, and C57BL͞6) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5 ؊/؊ mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL͞6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5 ؊/؊ mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.anabolic ͉ osteoporosis ͉ therapy

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…73 Nevertheless, the concept of bypassing the genetic defects of Wnt ligand/ receptors and targeting the downstream pathway may also be of value in developing treatment strategies for other diseases with defective Wnt signaling, such as osteoporosis. 74 …”

Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage

“…While there is agreement that inhibition of GSK-3 leads to enhanced bone mass, (14,16) the mechanism by which this occurs is controversial-whether this is due to enhanced drive to differentiation to osteoblasts and/or inhibition of osteoclast differentiation. We have shown that inhibition of GSK-3 blocks preadipocyte differentiation and enhances osteoblast differentiation in vivo despite progenitors with both potentials being amplified.…”

“…In vitro studies have used MSC-like cell lines (13)(14)(15) or primary human MSCs isolated and expanded in vitro under different culture conditions, (9,10,12) mostly in the absence of environmental signals. In vivo studies relied on lossand gain-of-function approaches, (13,16) leading to the presence or absence of factors well beyond physiologic levels, or relied on the use of nonselective GSK-3 inhibitors such as lithium chloride. (10,16) In this study we hypothesized that activation of canonical Wnt signaling by an inhibitor of GSK-3 promotes in vivo bone formation as a result of expansion of the mesenchymal progenitor cell compartment.…”

“…In vivo studies relied on lossand gain-of-function approaches, (13,16) leading to the presence or absence of factors well beyond physiologic levels, or relied on the use of nonselective GSK-3 inhibitors such as lithium chloride. (10,16) In this study we hypothesized that activation of canonical Wnt signaling by an inhibitor of GSK-3 promotes in vivo bone formation as a result of expansion of the mesenchymal progenitor cell compartment. To address this hypothesis, we used a novel selective inhibitor of GSK-3a/b, AR28, and studied the effects on proliferation and differentiation of mesenchymal progenitors in vivo.…”

The pathogenesis of the bone disease of multiple myeloma

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