Imperfect osteogenesis (O) refers to a group of rare genetic bone disorders which lead to the formation of fragile bone. In patients with OI, the matrix that makes up the bone has proven to be abnormal, resulting in increased risk of fractures. The genetic mutations affecting the biosynthesis of the protein of the collagen matrix in osteoblasts, or cells forming bones, were involved in the OI. However, the role of ripe bone cells of osteocytes derived from osteoblasts in the pathogenesis of the oi remains clear.
Specificity 7 (SP7) protein, coded by SP7 The gene is an important transcription factor which regulates the formation of healthy bones. Recent studies in patients have revealed that SP7 Mutations, such as the substitution of arginine with cysteine (R316C), can lead to a lower number of osteocytes or an abnormal morphology of osteocytes in bone tissue.
To shed light on the underlying mechanisms involved in the 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 of the endocrine unit of Massachusetts General Hospital, Harvard Medical School, United States, conducted an in-depth study by using a new mouse model. In their study, they developed a genetically modified model of mouse containing the SP7 R342C Mutation (Arginine’s amino acid is located in position 342 in mice). Their search results were published online on July 19, 2025 in volume 13 of the journal Bone search.
Initially, scientists used an advanced gene editing technique called igonad to generate mice with the SP7R342C mutation. The examination of the mutant femur of mouse femur via a micro-calculated tomography (micro-CT) revealed a reduced bone mineral density, a slight trabecular bone volume fraction and an increase in cortical porosity pores or channels in the external layer of the bone. “” These results are consistent with the skeletal phenotypes observed in patients with homozygous mutation SP7 R316C, “ Said Dr. Wang, explaining the advantages of using this mutant mouse model to study the OI.
Subsequently, the research team plunged into the bone renovation process in SP7R342C mouse. Bone remodeling generally implies the degradation of mature bone tissues and mineralized by osteoclasts (special cells which dissolve the damaged and old bone tissue) followed by the formation of a new bone matrix by osteoblasts. Interesting, in mice with the SP7R342C An abnormal mutation, an abnormal bone renovation process with increased intracortical bone training has been observed.
In addition, the number of elongated structures of dendrites of osteocytes which contribute to the regulation of bone remodeling have been reduced in mutant mice. An additional genomic analysis of the cells obtained from the external layer of the humerus bone revealed that Tumor necrosis factor Member of SuperFamille 11 (Tnfsf11) The gene, important for the formation of osteoclasts and the bone resorption activity, has been strongly expressed in mutant mice. Alarming, apoptosis (programmed cell death) of osteocytes was raised in these mutant mice.
The scientists then turned their attention to the sequencing of ribonucleic acid (RNA-SEQ) to identify the specific genes which were deregulated by the R342C mutation. Complete RNA analysis of the isolated bone cells in the Humerus of Females mutant mice showed that 1,079 genes were regulated upwards and that 920 genes were downward regulated. In particular, 22 genes linked to osteocytes were deregulated in mutant mice.
Finally, to clarify the relationship between the defects of osteocyte dendritis and abnormal bone absorption in SP7R342C Mouses, researchers injected mutant mice with osteoprotegerine-fc (OPG-FC). Sharing more details on the study, says Dr. Wein, “We do not know if the faults of morphology of osteocytes and apoptosis leads to bone resorption, or if an activity of increased osteoclastic causes defects of morphology of osteocytes”. After treatment with OPG-FC to inhibit the bone resorption process, cortical porosity has been reduced in mutant mice, but the dendrite defects of osteocytes could not be repaired.
In summary, the development of this mutant mouse model to study the OI provides an experimental platform to study the molecular mechanisms involved in bone defects and can help facilitate the discovery of new therapeutic approaches to treat bone disorders.
