Mice Deficient in NF-κB p50 and p52 or RANK Have Defective Growth Plate Formation and Post-natal Dwarfism

Abstract

NF-κBp50/p52 double knockout (dKO) and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism. In contrast, Op/Op mice, which form few osteoclasts, and Src KO mice, which have osteoclasts with defective resorptive function, are osteopetrotic, but they are not dwarfed. Here, we compared the morphologic features of long bones from p50/p52 dKO, RANK KO, Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths. We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2–3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone. This growth plate abnormality disappears when animals become older, but their dwarfism persists. Op/Op or Src KO mice have relatively normal growth plate morphology. In-situ hybridization study of long bones from p50/p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-expressing chondrocytes. Treatment of micro-mass chondrocyte cultures with RANKL did not affect expression levels of type 2 collagen and Sox9, markers for proliferative chondrocytes, but RANKL reduced the number of type 10 collagen-expressing hypertrophic chondrocytes. Thus, RANK/NF-κB signaling plays a regulatory role in post-natal endochondral ossification that maintains hypertrophic conversion and prevents dwarfism in normal mice.

CHIP regulates skeletal development and postnatal bone growth

“…It is known that NF‐κB controls growth plate cartilage development. In NF‐κB p50/p65 double KO mice, osteoclast formation is severely impaired leading to defects in the resorption of calcified cartilage and largely expanded hypertrophic cartilage zone at the postnatal stage (Xing et al, ). In this study, we found that growth plate cartilage development relatively normal in postnatal Chip CMV and Chip OsxER KO mice.…”

“…Nuclear factor-κB (NF-κB) signaling controls osteoclast formation (Boyce, Yao, & Xing, 2010) and is involved in the process of removal of calcified cartilage. In NF-κB p50/p65 double knockout (KO) mice, osteoclast formation is severely impaired leading to defects in the resorption of calcified cartilage and largely expanded hypertrophic zone at the postnatal stage (Xing, Chen, & Boyce, 2013).…”

Palmitoleic Acid Inhibits RANKL-Induced Osteoclastogenesis and Bone Resorption by Suppressing NF-κB and MAPK Signalling Pathways

“…NF-κB deficient mice have been shown to have no osteoclasts and develop severe osteopetrosis [37]. The MAPKs, p-38 [38], JNK1 [39], and ERK have all been shown to be activated when RANK is stimulated and are critical to osteoclast formation [36].…”

Arachidonic Acid and Docosahexaenoic Acid Suppress Osteoclast Formation and Activity in Human CD14+ Monocytes, In vitro

“…Studies have shown that the incorporation of ω-3 LCPUFAs into the cellular membrane is known to affect toll-like receptor 4 (TLR4) which can down-regulate NF-κB expression [ 38 ]. Down-regulation of NF-κB may have an effect on osteoclasts as it is known to activate osteoclast formation and function through the activation of NFATc1 [ 39 ], the master regulator of osteoclast formation and function.…”