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Increased NF-κB Activity in Osteoprogenitor-Lineage Cells Impairs the Balance of Bone Versus Fat in the Marrow of Skeletally Mature Mice

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Abstract

“Senile osteoporosis” is defined as significant aging-associated bone loss and is accompanied by increased fat in the bone marrow. The proportion of adipocytes in the bone marrow is inversely correlated with bone formation and is associated with increased risk of fracture. NF-κB is a transcription factor that functions as a master regulator of inflammation and bone remodeling. NF-κB activity increases during aging; furthermore, constitutive activation of NF-κB significantly impairs skeletal development in neonatal mice. However, the effects of NF-κB activation using a skeletally mature animal model have not been examined. In the current study, an osteoprogenitor (OP)-specific, doxycycline-regulated NF-κB-activated transgenic mouse model (iNF-κB/OP) was generated to investigate the role of NF-κB in bone remodeling in skeletally mature mice. Reduced osteogenesis in the OP-lineage cells isolated from iNF-κB/OP mice was only observed in the absence of doxycycline in vitro. Bone mineral density in the metaphyseal regions of femurs and tibias was reduced in iNF-κB/OP mice. No significant differences in bone volume fraction and cortical bone thickness were observed. Osmium-stained bone marrow fat was increased in epiphyseal and metaphyseal areas in the tibias of iNF-κB/OP mice. These findings suggest that targeting NF-κB activity as a therapeutic strategy may improve bone healing and prevent aging-associated bone loss in aged patients.

Lay Summary

“Senile osteoporosis” denotes significant aging-associated bone loss from the axial and peripheral skeleton and is accompanied by increased fat in the bone marrow. This imbalance in osteogenesis and adipogenesis is associated with an increased incidence of fragility fractures of the spine, hip, knee, shoulder, and wrist. NF-κB is a key regulator of bone remodeling. Increased NF-κB activity was found in many organs during the natural aging process. Clarification of the specific effect of increased NF-κB activity on osteoprogenitors during aging will delineate novel therapeutic approaches to mitigate the adverse effects of chronic inflammation and suppressed bone formation in aging-associated osteoporosis.

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Funding

This work was supported by NIH grant 1R01AR063717 and the Ellenburg Chair in Surgery at Stanford University. J.P. was supported by a grant from the Jane and Aatos Erkko Foundation.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA

    Tzuhua Lin, Jukka Pajarinen, Yusuke Kohno, Akira Nabeshima, Laura Lu, Karthik Nathan, Zhenyu Yao & Stuart Goodman

  2. Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA

    Joy Y. Wu

  3. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Stuart Goodman

  4. Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Redwood City, CA, 94063, USA

    Stuart Goodman

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  1. Tzuhua Lin
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Lin, T., Pajarinen, J., Kohno, Y. et al. Increased NF-κB Activity in Osteoprogenitor-Lineage Cells Impairs the Balance of Bone Versus Fat in the Marrow of Skeletally Mature Mice. Regen. Eng. Transl. Med. 6, 69–77 (2020). https://doi.org/10.1007/s40883-019-00112-7

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