Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism

Abstract

Wnt10b is an established regulator of mesenchymal stem cell (MSC) fate that inhibits adipogenesis and stimulates osteoblastogenesis, thereby impacting bone mass in vivo. However, downstream mechanisms through which Wnt10b exerts these effects are poorly understood. Moreover, whether other endogenous Wnt ligands also modulate MSC fate remains to be fully addressed. In this study, we identify Wnt6 and Wnt10a as additional Wnt family members that, like Wnt10b, are downregulated during development of white adipocytes in vivo and in vitro, suggesting that Wnt6 and/or Wnt10a may also inhibit adipogenesis. To assess the relative activities of Wnt6, Wnt10a and Wnt10b to regulate mesenchymal cell fate, we used gain- and loss-of function approaches in bipotential ST2 cells and in 3T3-L1 preadipocytes. Enforced expression of Wnt10a stabilizes β-catenin, suppresses adipogenesis and stimulates osteoblastogenesis to a similar extent as Wnt10b, whereas stable expression of Wnt6 has a weaker effect on these processes than Wnt10a or Wnt10b. In contrast, knockdown of endogenous Wnt6 is associated with greater preadipocyte differentiation and impaired osteoblastogenesis than knockdown of Wnt10a or Wnt10b, suggesting that, amongst these Wnt ligands, Wnt6 is the most potent endogenous regulator of MSC fate. Finally, we show that knockdown of β-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by Wnt6, Wnt10a or Wnt10b. Potential mechanisms whereby Wnts regulate fate of MSCs downstream of β-catenin are also investigated. In conclusion, this study identifies Wnt10a and Wnt6 as additional regulators of MSC fate and demonstrates that mechanisms downstream of β-catenin are required for Wnt6, Wnt10a and Wnt10b to influence differentiation of mesenchymal precursors.

Variability in dentofacial phenotypes in four families with WNT10A mutations

“…12,25 Until recently, data suggestive for a possible molecular underpinning of this phenomenon was however lacking. In their study in mice, Cawthorn et al 26 identified Wnt10a as well as Wnt10b and Wnt6, as potent endogenous regulators of mesenchymal stem cell fate, inhibiting adipogenesis and stimulating osteoblastogenesis through a b-catenindependent mechanism. We therefore hypothesize that mutant WNT10A ligand proteins not being able to initiate the appropriate signaling in the WNT signaling pathway, not only fail to initiate tooth development, but also disrupt the process of osteoblastogenesis ultimately leading to reduced bone mass formation.…”

“…The proband is a 9-year-old boy of Belgian descent (patient A II-2) with TA of 22 permanent teeth. Only six permanent teeth (16,11,21,26, 36 and 46) developed while his mother reported that her son had a complete deciduous dentition. The upper permanent central incisors are conically shaped and the upper first permanent molars are hypoplastic.…”

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

“…Previous studies have made good progress in documenting the changes in Wnt expression that accompany adipogenesis (27,41), and their mechanisms of signaling through cell-surface Fz receptors (42). For example, it has been shown that Wnt10b-but not Wnt3a-RNA is present at a relatively high level in human mesenchymal precursor cells (27) and preadipocytes (41), and that Wnt10b RNA levels fall quite dramatically in these cell types following addition of adipocytogenic mixtures (43).…”

“…For example, it has been shown that Wnt10b-but not Wnt3a-RNA is present at a relatively high level in human mesenchymal precursor cells (27) and preadipocytes (41), and that Wnt10b RNA levels fall quite dramatically in these cell types following addition of adipocytogenic mixtures (43). Conversely, enforced Wnt10b expression in ST2 marrow-derived stromal cells (44) and 3T3-L1 preadipocytes suppresses adipocyte differentiation and lowers Pparγ RNA, even before adipogenesis is induced (41,43). Moreover, high-level Wnt10b expression in transgenic mice reduces both Pparγ expression and WAT development but not adipocyte size (45).…”

Brown adipose tissue and bone

“…One potential mechanism for the interaction between BAT and bone is that the two tissues communicate via secreted factors. The authors evaluated the gene expression levels of some known regulators of bone anabolism (Wnt10b (wingless-type MMTV integration site family, member 10B), 44,45 Igfbp2 (insulin-like growth factor binding protein 2), 46 Igf1 (insulin-like growth factor 1), 47 Bmp4, 48 Adipoq (adiponectin) 49 and Angpt2 (angiopoietin 2)) in both adipose tissue and bone marrow adipocytes with elevated FOXC2 levels. They found that the expression levels of the genes encoding the endocrine factors ADIPOQ, IGF1 and IGFBP2, as well as the paracrine factors WNT10B, BMP4 and ANGPT2 were all upregulated in both adipose tissue and bone marrow adipocytes with elevated FOXC2 levels.…”