Jansen's disease: bone abnormalities beyond chondrodysplasia.

Objective: This study aimed to assess changes in bone microarchitecture, bone formation and bone protein expression in two pediatric patients with Jansen metaphyseal chondrodysplasia (JMC), harboring the H223R-PTHR1 mutation.

Methods: Bone histomorphometry, immunohistochemistry and histologic analyses were conducted on iliac crest biopsy samples from two male siblings affected by JMC (ages 6 and 8 years) and 9 healthy control males of similar age, with normal kidney function.

Results: Both JMC patients displayed irregular bone architecture, increased osteoid, and a prolonged osteoid maturation process. While trabecular volume remained normal, immunohistochemical analysis demonstrated increased in PTH1R expression in both osteoblasts and fibroblastic cells on the bone surface. Cortical bone displayed areas of intense osteoclast activity and scattered marrow fibrosis. Remarkably, osteocytes in JMC patient samples had osteoid buildup within their lacunae and canaliculi that were both shorter and less abundant. DMP1 immunohistochemistry highlighted the abnormal canalicular network in patients. FGF23 staining in osteocytes was enhanced while sclerostin was diminished.

Conclusion: The H223R-PTH1R mutation in JMC patients leads to bone structural irregularities, hypomineralization, abnormal osteocyte morphology, and altered expression of osteocyte-derived proteins. These findings underscore the multifaceted impact of the mutant PTH1R on bone physiology and focus attention on the osteocyte as a cellular target for therapeutic intervention. Whether normalizing gene expression in osteocytes is possible and can improve bone health in JMC patients remains to be seen. Assessment of osteocyte morphology and function may provide novel diagnostic endpoints for future clinical trials with JMC therapeutics.