Wnt10b deficiency results in age-dependent loss of bone mass and progressive reduction of mesenchymal progenitor cells

Abstract

Wnt10b is a canonical Wnt ligand expressed in developing bone and has been linked to mesenchymal progenitor functions in mice and humans. Because Wnt signaling has been shown to play an important role in progenitor maintenance in a variety of adult tissues, we examined bone deposition and growth rates throughout postnatal development in Wnt10b-null mice. Using bone histomorphometry and micro–computed tomographic (µCT) studies, we demonstrate that trabecular bone deposition is slightly enhanced in Wnt10b-null mice at 1 month of age, followed by progressive loss with age. Importantly, we find that Wnt10b is required for maintenance of adult bone density in multiple backgrounds of inbred mice and that both copies of the Wnt10b gene are required to maintain normal bone density in 6-month-old animals. We go on to show that the loss in trabecular bone in Wnt10b-null mice is associated with a reduction in the number of bone marrow–derived mesenchymal progenitors (MPCs) using in vitro colony-forming unit assays and marker analysis. Analysis of osteogenic gene expression in primary bone marrow stromal cells demonstrated reductions in expression of several osteoblast differentiation markers. Taken together, our results indicate that Wnt10b is uniquely required for maintenance of mesenchymal progenitor activity in adult bone. The results show the significance of studying individual Wnt ligands and their potentially unique contribution in the context of aging and disease. © 2010 American Society for Bone and Mineral Research.

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

“…Importantly, the increased bone mass phenotype was observed in both cancellous and cortical bone compartments of either sex, which is in line with the impact of Sost/sclerostin deficiency and its pharmacologic blockade on the skeleton (37)(38)(39)(40)(41)(42). This finding differs from the selective impact that individual WNTs can have on either bone compartment (43)(44)(45). In addition, we found increased osteoblast function coupled with a nonsignificant decrease in osteoclast activity as a result of Lrp4 osteoblast/osteocyte deficiency in line with the phenotype of Sost knockout mice (37,38).…”

Wnts produced by Osterix-expressing osteolineage cells regulate their proliferation and differentiation

“…Although Wnt10b and Wnt7b are two of the Wnts most commonly associated with bone biology, and Wnt10b is abundantly expressed based on our ISH survey (Wnt7b was moderately expressed), knocking out either Wnt did not produce a drastic skeletal phenotype: Wnt10b knockout mice exhibited mild age-progressive osteopenia (46) and Wnt7b knockout mice were viable and had reduced ossification (53). Hence, to observe more severe bone defects, multiple Wnts have to be knocked out simultaneously, or the Wnt secretion or posttranslational modification process has to be targeted to affect the availability of Wnt ligands.…”

“…For example, although Wnt10b is broadly expressed throughout the bone, Wnt4 expression is noticeably higher around the trabecular endosteum compared with the cortical endosteum, and Wnt7b is more highly expressed in the perichondrium than the trabecular and cortical bone regions. The overall most highly expressed Wnt gene is Wnt10b, which is widely considered one of the most important Wnts in bone biology (41)(42)(43)(44)(45)(46). The overall expression levels of all of the Wnt genes are tabulated in Table S1 and ranked in Table S2.…”

Osteogenesis of Adipose-Derived Stem Cells

“…Si et al found that tightly regulated CCN1/Cyr61 expression may play an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells (39). Stevens et al indicated that Wnt10b, as the only Wnt ligand linking to mesenchymal progenitor function in both humans and mice, is uniquely required for maintenance of mesenchymal progenitor activity in adult bone (40). Some studies revealed that noncanonical Wnt signaling could also play a role in osteogenic differentiation.…”