Osteogenesis imperfecta (OI) refers to a group of rare genetic bone disorders that results in the formation of fragile bones. In patients with OI, the matrix that makes up the bone has been found to be abnormal, leading to an increased risk of fractures. Genetic mutations affecting collagen matrix protein biosynthesis in osteoblasts, or bone-forming cells, have been implicated in OI. However, the role of osteocytes—mature bone cells derived from osteoblasts—in OI pathogenesis remains unclear.
Specificity protein 7 (Sp7), encoded by Sp7 gene is an important transcription factor that regulates the formation of healthy bones. Recent studies in patients with OI have revealed that rare SP7 mutations, such as the substitution of arginine with cysteine (R316C), can result in lower number of osteocytes or abnormal osteocyte morphology within bone tissue.
To shed light on the underlying mechanisms involved in OI, caused by Sp7 R316C mutation, a team of researchers led by Dr. Jialiang S. Wang from the University of Texas Southwestern Medical Center, USA and Dr. Marc N. Wein from the Endocrine Unit of Massachusetts General Hospital, Harvard Medical School, USA has conducted an in-depth study using a novel mouse model. In their study, they developed a genetically modified mouse model containing the Sp7 R342C mutation (the arginine amino acid is located at position 342 in mice). Their research findings were published online on July 19, 2025 in Volume 13 of the journal Bone Research .
Initially, the scientists employed an advanced gene editing technique called iGONAD to generate mice with the Sp7R342C mutation. Examination of the femur bone of mutant mice via micro-computed tomography (micro-CT) revealed reduced bone mineral density, a lower trabecular bone volume fraction, and increased cortical porosity-pores or channels in the outer layer of the bone. "These findings are consistent with skeletal phenotypes observed in patients with homozygous Sp7 R316C mutation," says Dr. Wang, explaining the advantages of using this mutant mouse model for studying OI.
Subsequently, the research team delved into the bone-remodeling process in Sp7R342C mice. Bone remodeling typically involves the degradation of mature and mineralized bone tissue by osteoclasts (special cells that dissolve damaged and old bone tissue) followed by formation of new bone matrix by osteoblasts. Interestingly, in mice with the Sp7R342C mutation, an abnormal bone-remodeling process with increased intracortical bone resorption and formation was observed.
Furthermore, the number of osteocyte dendrites—elongated structures that help in regulation of bone remodeling—was reduced in the mutant mice. Additional genomic analysis of cells obtained from the outer layer of the humerus bone revealed that tumor necrosis factor superfamily member 11 (Tnfsf11) gene, important for osteoclast formation and bone-resorption activity, was highly expressed in mutant mice. Alarmingly, apoptosis (programmed cell death) of osteocytes was elevated in these mutant mice.
The scientists then turned their attention to ribonucleic acid sequencing (RNA-seq) to identify the specific genes that were dysregulated by the R342C mutation. Comprehensive RNA-seq analysis of bone cells isolated from the humerus of female mutant mice showed that 1,079 genes were up-regulated and 920 genes were down-regulated. Notably, 22 osteocyte-related genes were dysregulated in the mutant mice.
Finally, to clarify the relationship between osteocyte dendrite defects and abnormal bone resorption in Sp7R342C
