New Mouse Model Reveals Key Role Of Osteocytes In Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) refers to a group of uncommon familial bony disorders that results successful nan statement of vulnerable bones. In patients pinch OI, nan matrix that makes up nan bony has been recovered to beryllium abnormal, starring to an accrued consequence of fractures. Genetic mutations affecting collagen matrix macromolecule biosynthesis successful osteoblasts, aliases bone-forming cells, person been implicated successful OI. However, nan domiciled of osteocytes-mature bony cells derived from osteoblasts-in OI pathogenesis remains unclear.

Specificity macromolecule 7 (Sp7), encoded by Sp7 cistron is an important transcription facet that regulates nan statement of patient bones. Recent studies successful patients pinch OI person revealed that uncommon SP7 mutations, specified arsenic nan substitution of arginine pinch cysteine (R316C), tin consequence successful little number of osteocytes aliases abnormal osteocyte morphology wrong bony tissue.

To shed ray connected nan underlying mechanisms progressive successful OI, caused by Sp7 R316C mutation, a squad of researchers led by Dr. Jialiang S. Wang from nan University of Texas Southwestern Medical Center, USA and Dr. Marc N. Wein from nan Endocrine Unit of Massachusetts General Hospital, Harvard Medical School, USA has conducted an in-depth study utilizing a caller rodent model. In their study, they developed a genetically modified rodent exemplary containing nan Sp7 R342C mutation (the arginine amino acerb is located astatine position 342 successful mice). Their investigation findings were published online connected July 19, 2025 successful Volume 13 of nan diary Bone Research.

Initially, nan scientists employed an precocious cistron editing method called iGONAD to make mice pinch nan Sp7R342C mutation. Examination of nan femur bony of mutant mice via micro-computed tomography (micro-CT) revealed reduced bony mineral density, a little trabecular bony measurement fraction, and accrued cortical porosity-pores aliases channels successful nan outer furniture of nan bone. "These findings are accordant pinch skeletal phenotypes observed successful patients pinch homozygous Sp7 R316C mutation," says Dr. Wang, explaining nan advantages of utilizing this mutant rodent exemplary for studying OI.

Subsequently, nan investigation squad delved into nan bone-remodeling process successful Sp7R342C mice. Bone remodeling typically involves nan degradation of mature and mineralized bony insubstantial by osteoclasts (special cells that dissolve damaged and aged bony tissue) followed by statement of caller bony matrix by osteoblasts. Interestingly, successful mice pinch nan Sp7R342C mutation, an abnormal bone-remodeling process pinch accrued intracortical bony resorption and statement was observed.

Furthermore, nan number of osteocyte dendrites-elongated structures that thief successful regularisation of bony remodeling-was reduced successful nan mutant mice. Additional genomic study of cells obtained from nan outer furniture of nan humerus bony revealed that tumor necrosis facet superfamily personnel 11 (Tnfsf11) gene, important for osteoclast statement and bone-resorption activity, was highly expressed successful mutant mice. Alarmingly, apoptosis (programmed compartment death) of osteocytes was elevated successful these mutant mice.

The scientists past turned their attraction to ribonucleic acerb sequencing (RNA-seq) to place nan circumstantial genes that were dysregulated by nan R342C mutation. Comprehensive RNA-seq study of bony cells isolated from nan 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 successful nan mutant mice.

Finally, to explain nan narration betwixt osteocyte dendrite defects and abnormal bony resorption successful Sp7R342C mice, nan researchers injected mutant mice pinch osteoprotegerin-Fc (OPG-Fc). Sharing further specifications astir nan study, Dr. Wein says, "It is not known whether osteocyte morphology defects and apoptosis thrust bony resorption, aliases whether accrued osteoclast activity drives osteocyte morphology defects". Following curen pinch OPG-Fc to inhibit nan bone-resorption process, cortical porosity was reduced successful mutant mice, but nan osteocyte dendrite defects could not beryllium repaired.

In summary, nan improvement of this mutant rodent exemplary to study OI provides an experimental level to analyse nan molecular mechanisms progressive successful bony defects and tin thief facilitate nan find of caller therapeutic approaches for treating bony disorders.