IRX3 and IRX5 Inhibit Adipogenic Differentiation of Hypertrophic Chondrocytes and Promote Osteogenesis

• Published in: Journal of bone and mineral research Vol. 35; no. 12; pp. 2444 - 2457
• Main Authors: Tan, Zhijia, Kong, Mingpeng, Wen, Songjia, Tsang, Kwok Yeung, Niu, Ben, Hartmann, Christine, Chan, Danny, Hui, Chi‐chung, Cheah, Kathryn S.E.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2020; Wiley Subscription Services, Inc
• Subjects: Adipocytes; Adipogenesis - genetics; Animals; Bone marrow; BONE MODELING AND REMODELING; Cancellous bone; Cell Differentiation; CELL/TISSUE SIGNALING; CELLS OF BONE, GROWTH PLATE; CHONDROCYTE AND CARTILAGE BIOLOGY, MOLECULAR PATHWAYS; Chondrocytes; Chondrogenesis; Cortical bone; DEVELOPMENT; GENETIC ANIMAL MODELS; Homeodomain Proteins - genetics; Homeostasis; Mice; OSTEOBLASTS; Osteogenesis; TRANSCRIPTION FACTORS; Transcription Factors - genetics; Wnt protein; CELL/TISSUE SIGNALING; TRANSCRIPTION FACTORS; BONE MODELING AND REMODELING; CELLS OF BONE, GROWTH PLATE; GENETIC ANIMAL MODELS; DEVELOPMENT; OSTEOBLASTS; CHONDROCYTE AND CARTILAGE BIOLOGY, MOLECULAR PATHWAYS
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1002/jbmr.4132

ABSTRACT Maintaining the correct proportions of different cell types in the bone marrow is critical for bone function. Hypertrophic chondrocytes (HCs) and osteoblasts are a lineage continuum with a minor contribution to adipocytes, but the regulatory network is unclear. Mutations in transcription factors, IRX3 and IRX5, result in skeletal patterning defects in humans and mice. We found coexpression of Irx3 and Irx5 in late‐stage HCs and osteoblasts in cortical and trabecular bone. Irx3 and Irx5 null mutants display severe bone deficiency in newborn and adult stages. Quantitative analyses of bone with different combinations of functional alleles of Irx3 and Irx5 suggest these two factors function in a dosage‐dependent manner. In Irx3 and Irx5 nulls, the amount of bone marrow adipocytes was increased. In Irx5 nulls, lineage tracing revealed that removal of Irx3 specifically in HCs exacerbated reduction of HC‐derived osteoblasts and increased the frequency of HC‐derived marrow adipocytes. β‐catenin loss of function and gain of function specifically in HCs affects the expression of Irx3 and Irx5, suggesting IRX3 and IRX5 function downstream of WNT signaling. Our study shows that IRX3 and IRX5 regulate fate decisions in the transition of HCs to osteoblasts and to marrow adipocytes, implicating their potential roles in human skeletal homeostasis and disorders. Fate decision of hypertrophic chondrocyte is controlled by Irx3 and Irx5. With normal expression of Irx3 and Irx5, hypertrophic chondrocytes preferentially differentiate into Col1a1+ osteoblasts, and few are differentiated into Perilipin+ adipocytes. Upon deletion of Irx3 and Irx5, osteogenesis of hypertrophic chondrocyte is inhibited and adipogenesis is promoted, which causes repaired bone formation and increased bone marrow adipose tissue amount. © 2020 American Society for Bone and Mineral Research.