Global and Conditional Disruption of the IIgf-I/I Gene in Osteoblasts and/or Chondrocytes Unveils Epiphyseal and Metaphyseal Bone-Specific Effects of IGF-I in Bone

• Published in: Biology (Basel, Switzerland) Switzerland), 2023-09, Vol.12 (9)
• Main Authors: Xing, Weirong, Kesavan, Chandrasekhar, Pourteymoor, Sheila, Mohan, Subburaman
• Format: Article
• Language: English
• Subjects: Analysis; Bones; Density; Ethylenediaminetetraacetic acid; Genes; Genetic engineering
• ISSN: 2079-7737; 2079-7737
• DOI: 10.3390/biology12091228

To investigate the relative importance of IGF-I expression in various types of bone cells for endochondral ossification, we examined the trabecular bone phenotypes at the distal femoral epiphysis and the secondary spongiosa of male mice with a global deletion of the Igf-I gene, as well as the conditional disruption of Igf-I in osteoblasts, chondrocytes, and osteoblasts/chondrocytes and their corresponding control littermates. We demonstrated that the disruption of Igf-I globally attenuated bone size much more severely than conditional abrogation in osteoblasts. Trabecular bone mass was lower in the secondary spongiosa of all four knockout mouse lines studied. Global Igf-I abrogation, but not conditional loss of Igf-I, locally diminished trabecular bone mass in the epiphysis. Our findings provide evidence that local and endocrine IGF-I actions in bone are pleiotropic and dependent on cell type and the bone compartment in which IGF-I acts. To evaluate the relative importance of IGF-I expression in various cell types for endochondral ossification, we quantified the trabecular bone at the secondary spongiosa and epiphysis of the distal femur in 8–12-week-old male mice with a global knockout of the Igf-I gene, as well as the conditional deletion of Igf-I in osteoblasts, chondrocytes, and osteoblasts/chondrocytes and their corresponding wild-type control littermates. The osteoblast-, chondrocyte-, and osteoblast/chondrocyte-specific Igf-I conditional knockout mice were generated by crossing Igf-I floxed mice with Cre transgenic mice in which Cre expression is under the control of either the Col1α2 or Col2α1 promoter. We found that the global disruption of Igf-I resulted in 80% and 70% reductions in bone size, defined as total volume, at the secondary spongiosa and epiphysis of the distal femur, respectively. The abrogation of Igf-I in Col1α2-producing osteoblasts but not Col2α1-producing chondrocytes decreased bone size by 25% at both the secondary spongiosa and epiphysis. In comparison, the deletion of the Igf-I globally or specifically in osteoblasts or chondrocytes reduced trabecular bone mass by 25%. In contrast, the universal deletion of Igf-I in all cells, but not the conditional disruption of Igf-I in osteoblasts and/or chondrocytes reduced trabecular bone mass in the epiphysis. The reduced trabecular bone mass at the secondary spongiosa in osteoblast- and/or chondrocyte-specific Igf-I conditional knockout mice is caused by the reduced trabecular number a