IKKβ in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5

Abstract

IκB kinase β (IKKβ) is a catalytic subunit of the IKK complex, which activates nuclear factor-κB (NF-κB). Although its role in osteoclastogenesis is well established, the role of IKKβ in bone formation is poorly understood. Here, we report that conditional knockout of Ikkβ in limb bud mesenchymal cells results in the upregulation of monocyte chemoattractant protein-5 (MCP-5) in the perichondrium, which in turn inhibits the growth of longitudinal bone by compromising chondrocyte hypertrophy and increasing the apoptosis of chondrocytes within the growth plate. Contrary to expectations, IKKβ in cells of chondrocyte or osteoblast lineage was dispensable for bone growth. On the other hand, ex vivo experiments confirmed the role of MCP-5 in the growth of longitudinal bone. Furthermore, an in vitro study demonstrated that the action of IKKβ on MCP-5 is cell autonomous. Collectively, our results provide evidence for a previously unrecognized role of IKKβ in the regulation of the growth plate that is mediated through stimulation-independent downregulation of MCP-5 in the perichondrium.

Endogenous Tissue Engineering for Chondral and Osteochondral Regeneration: Strategies and Mechanisms

“…Initially, chemokines, such as chemoattractant protein-5 (MCP-5) in the perichondrium, regulate chondrocyte hypertrophy. IκB kinase β can suppress MCP-5 expression, promoting chondrocyte hypertrophy and compromising chondrocyte apoptosis through the IKKβ/TβRII–MCP-5 axis. , Growth factors, such as PDGF-BB derived from preosteoclasts, are closely associate with AC hypertrophy, regulating chondrocytes via aberrant angiogenesis . Osteoclasts are recruited during this process, infiltrating the region of AC hypertrophy, resulting in calcified AC microfissures and focal subchondral bone loss .…”

CCL12 induces trabecular bone loss by stimulating RANKL production in BMSCs during acute lung injury

“…The same research group further revealed the potential efficacy of antagonizing CCR2 during the early stages of OA to slow the progression of postinjury OA and improve pain symptoms 15 . Another study provided evidence that CCL12 in the perichondrium was downregulated by IKKβ and involved in the endochondral ossification of the growth plate 16 . However, there have been no reports concerning the role of CCL12 in osteoporosis.…”