TY - JOUR
T1 - Common Histological Features Suggesting Enchondral Ossification Pathways in Calciphylaxis of Various Origins
T2 - A Study of Human Subcutaneous Tissue Biopsies
AU - Aberger, Simon
AU - Findenig, Barbara
AU - Beil, Jane
AU - Aichinger, Nicole
AU - Koller, Josef
AU - Vermeer, Cees
AU - Schurgers, Leon
AU - Theuwissen, Elke
AU - More, Elena
AU - Franzen, Michael
AU - Kronberger, Cornelia
AU - Salmhofer, Hermann
PY - 2023
Y1 - 2023
N2 - Calciphylaxis is a rare, yet underdiagnosed condition causing high mortality in patients with severe renal and cardiovascular disease. Since knowledge of the patho physiology of calciphylaxis is limited, a differential analysis of histological alterations in patient subgroups with various comorbidities might expose different disease phenotypes and allow deeper insights into the pathophysiology of the condition. Histological markers of osteogenesis and calcification were investigated in a group of 18 patients with clinically and histologically verified calciphylaxis, using immunohistochemical staining. Analysis of staining intensity and distribution of marker proteins in histological structures was performed to evaluate distinct patterns between subgroups with different clinical comorbidities in comparison with a control group. In all cases, immunohistochemical staining for bone matrix proteins, bone-morphogenic proteins and matrixGla proteins co-localized with subcutaneous vascular and interstitial calcifications. Significant expression of bone-morphogenic protein-7 and active matrixGla protein was observed. Mortality was associated with renal comorbidities and increased expression of bone-morphogenic protein-7. However, no distinct histological patterns were found between subgroups with renal disease, warfarin intake or coexisting mi cro-and macro-angiopathies. The upregulation of osteogenic markers (including bone-morphogenic protein-7) plays a major role in the development of calciphylaxis. Clinical outcome correlates with kidney function and phosphate handling, suggesting different pathophysiological mechanisms. However, biopsy at late-stage disease shows a common histological phenotype, involving enchondral ossification.SIGNIFICANCECalciphylaxis is a rare, calcifying, occlusive vessel disease with different aetiopathological origins and high mortality. Previous histological studies have shown upregulation of bone-morphogenic proteins, bone matrix proteins, and dysbalance of calcification inhibitors. This study confirmed the upregulation of osteogenic markers, including the first evidence of upregulation of bone-morphogenic-protein 7, in calciphylaxis. Renal function, sequential comorbidities, phosphate handling and high expression of bone-morphogenic protein-7 were identified as predictors of clinical outcome. However, the histo logical appearance did not differ between patients with different comorbidities. Therefore, disease evolution may have different pathophysiological drivers with a common pathophysiological endpoint. This underlines the need for individualization of multimodal treatment in calciphylaxis.
AB - Calciphylaxis is a rare, yet underdiagnosed condition causing high mortality in patients with severe renal and cardiovascular disease. Since knowledge of the patho physiology of calciphylaxis is limited, a differential analysis of histological alterations in patient subgroups with various comorbidities might expose different disease phenotypes and allow deeper insights into the pathophysiology of the condition. Histological markers of osteogenesis and calcification were investigated in a group of 18 patients with clinically and histologically verified calciphylaxis, using immunohistochemical staining. Analysis of staining intensity and distribution of marker proteins in histological structures was performed to evaluate distinct patterns between subgroups with different clinical comorbidities in comparison with a control group. In all cases, immunohistochemical staining for bone matrix proteins, bone-morphogenic proteins and matrixGla proteins co-localized with subcutaneous vascular and interstitial calcifications. Significant expression of bone-morphogenic protein-7 and active matrixGla protein was observed. Mortality was associated with renal comorbidities and increased expression of bone-morphogenic protein-7. However, no distinct histological patterns were found between subgroups with renal disease, warfarin intake or coexisting mi cro-and macro-angiopathies. The upregulation of osteogenic markers (including bone-morphogenic protein-7) plays a major role in the development of calciphylaxis. Clinical outcome correlates with kidney function and phosphate handling, suggesting different pathophysiological mechanisms. However, biopsy at late-stage disease shows a common histological phenotype, involving enchondral ossification.SIGNIFICANCECalciphylaxis is a rare, calcifying, occlusive vessel disease with different aetiopathological origins and high mortality. Previous histological studies have shown upregulation of bone-morphogenic proteins, bone matrix proteins, and dysbalance of calcification inhibitors. This study confirmed the upregulation of osteogenic markers, including the first evidence of upregulation of bone-morphogenic-protein 7, in calciphylaxis. Renal function, sequential comorbidities, phosphate handling and high expression of bone-morphogenic protein-7 were identified as predictors of clinical outcome. However, the histo logical appearance did not differ between patients with different comorbidities. Therefore, disease evolution may have different pathophysiological drivers with a common pathophysiological endpoint. This underlines the need for individualization of multimodal treatment in calciphylaxis.
KW - bone morphogenic proteins
KW - calcific uraemic arteriolopathy
KW - enchondral ossification
KW - rare diseases
KW - VASCULAR CALCIFICATION
KW - BONE
KW - EXPRESSION
KW - PROTEIN
KW - INHIBITORS
U2 - 10.2340/actadv.v103.5755
DO - 10.2340/actadv.v103.5755
M3 - Article
C2 - 37428027
SN - 0001-5555
VL - 103
JO - Acta Dermato-Venereologica
JF - Acta Dermato-Venereologica
IS - 1
M1 - adv5755
ER -