Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures

Abstract

The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin

“…We show that a twofold induction in OPG mRNA may have the potential to alter bone homeostasis. In support of our work, Movérare-Skrtic et al (2014) also demonstrated that a twofold reduction in OPG was associated with diminished bone strength. In vivo, we found that enhanced trabecular bone volume was associated with a threefold increase in OPG mRNA expression.…”

“…For hypoxia treatments, cells were plated 12 h prior to placement into a hypoxia chamber (Invivo2-400, Ruskin Technologies) and maintained at 0.5% oxygen for 24 h. All endpoints measured for cells under hypoxic conditions were compared with cells cultured under normoxic conditions (21% oxygen). Cocultures were prepared as previously described (Movérare-Skrtic et al 2014). Briefly, mouse calvarias osteoblast cells from PHD2 fl/fl ; PHD3 fl/fl mice were treated with adeno-CRE or control virus for 24 h as previously described (Wang et al 2007;see below).…”

Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis

“…In addition, previous studies showed that osteocytes regulate osteoclastogenesis by secreting RANKL and osteoprotegerin that are downstream targets of canonical β-catenin-dependent WNT signaling (7,(32)(33)(34)(35)(36). Our current study and other previous studies also strongly suggest that there is specificity between WNT ligands and downstream cell signaling targets (10,12,14,42). Hence, the osteocyte can be seen increasingly as the central regulator of bone mass.…”

“…The rescued bone phenotypes of Wnt1 sw/sw mice strongly suggest that other WNT ligands, including excellent candidates such as WNT16, WNT10b, and WNT7b, can compensate for loss of Wnt1 in Wnt1 sw/sw mice (10)(11)(12)(13)(14)(15)(16)(17). Despite the potential redundancy of multiple WNT ligands that affect bone formation, the incomplete restoration of bone volume by Scl-Ab treatment in Wnt1 sw/sw mice suggests that WNT1 clearly has a critical function in bone homeostasis.…”

“…Genetic studies of LRP5 in human and mouse strongly suggest that canonical Wnt signaling regulates postnatal bone formation (2)(3)(4)(5). Further genetic studies with β-catenin and other Wnt ligands using various mouse models provided additional evidence that corroborate the critical function of Wnt signaling in skeletal development and bone homeostasis (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Several recent studies also reported that Wnt signaling directly regulates osteoclast function (18)(19)(20)(21)(22).…”