Mineralized Peyronie’s plaque has a phenotypic resemblance to bone

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madman

Super Moderator
Abstract

Mineralized Peyronie’s plaque (MPP) impairs penile function. The association, colocalization, and dynamic interplay between organic and inorganic constituents can provide insights into the biomineralization of Peyronie's plaque. Human MPPs (n = 11) were surgically excised, and the organic and inorganic constituents were spatially mapped using multiple high-resolution imaging techniques. Multiscale image analyses resulted in spatial colocalization of elements within a highly porous material with heterogenous composition, lamellae, and osteocytic lacuna-like features with a morphological resemblance to bone. The lower (520 ±179 mg/cc) and higher (1024 ± 155 mg/cc) mineral density regions were associated with higher (11%) and lower (7%) porosities in MPP. Energy-dispersive X-ray and micro-X-ray fluorescent spectroscopic maps in the higher mineral density regions of MPP revealed higher counts of calcium (Ca) and phosphorus (P), and a Ca/P ratio of 1.48 ± 0.06 similar to bone. More importantly, higher counts of zinc (Zn) were localized at the interface between softer (more organic to inorganic ratio) and harder (less organic to inorganic ratio) tissue regions of MPP and adjacent softer matrix, indicating the involvement of Zn-related proteins and/or pathways in the formation of MPP. In particular, dentin matrix protein-1 (DMP-1) was colocalized in a matrix rich in proteoglycans and collagen that contained osteocytic lacuna-like features. This combined materials science and biochemical with correlative microspectroscopic approach provided insights into the plausible cellular and biochemical pathways that incite mineralization of an existing fibrous Peyronie’s plaque.




Statement of Significance

Aberrant human penile mineralization is known as mineralized Peyronie’s plaque (MPP) and often results in a loss of form and function.
This study focuses on investigating the spatial association of matrix proteins and elemental composition of MPP by colocalizing calcium, phosphorus, and trace metal zinc with dentin matrix protein 1 (DMP-1), acidic proteoglycans, and fibrillar collagen along with the cellular components using high-resolution correlative microspectroscopic techniques. Spatial maps provided insights into cellular and biochemical pathways that incite the mineralization of fibrous Peyronie’s plaque in humans.




1. INTRODUCTION

Aberrant human penile mineralization is known as mineralized Peyronie’s plaque (MPP) [1]. The genesis of MPP is reliant on the formation of fibrotic plaque in the tunica albuginea of the penile corpora cavernosum [2, 3]. Fibrillar proteins including collagen, elastin, and fibronectin were identified in the fibrotic plaque of the MPP [4, 5]. MPP commonly forms on the dorsal aspect of the penis and can result in a loss of form and thereby function [6].

The biomineralization process of MPP [1] resembles heterotopic ossification (HO). HO results from fibroblast proliferation stimulated by the repetitive mechanical insult to the tissue followed by microvascular injury and subsequent deposition of fibrin [7, 8]. MPP results from the differentiation of the fibroblasts in the tunica albuginea into myofibroblasts [9]. Myofibroblasts [10], smooth muscle cells [11, 12], and pericytes [13, 14] in blood vessels have been shown to undergo differentiation to osteogenic lineage in vitro. These cells are thought to be the initiators of mineralization of the softer but inflamed matrices. This biochemical pathway is thought to be a biologically controlled biomineralization process culminating in an MPP. Surgical excision of MPP followed by mechanical therapy to restore penile form and function is the current clinical intervention [1]. Inflammation-related processes as well as the cation and anion recruitment including the metal ion Zn2+ are unknown. Various qualitative results focus on the ultrastructure of MPP [15-17]. Limited studies exist on the spatial-temporal localization of the biochemical and cytochemical markers of MPP and the surrounding soft tissue. Additionally, the spatial and chemical association of elements including calcium and phosphorus toward mineralization of collagen fibrils within the fibrotic plaque and the role of the neurovascular bundle in the subsequent formation of MPP following an insult are yet to be understood. As such, some questions to ask include 1) does MPP grow from a mineralized nodule, and 2) does it begin as a fibrotic tissue and mineralize with phenotypic resemblance to bone? This study focuses on investigating the spatial association of matrix proteins and elemental composition of MPP by colocalizing Ca, P, and trace metal Zn with dentin matrix protein 1 (DMP-1), acidic proteoglycans, and fibrillar collagen along with the cellular components using high resolution correlative microspectroscopic techniques. Spatial maps of colocalized organic and inorganic constituents will provide insights into plausible biomineralization pathways of fibrotic Peyronie’s plaque and help guide effective clinical interventions.




*In summary, the correlative microspectroscopic approach on quantitative spatial mapping of MD, elements, and matrix alluded to MPP as HO. Both MPP and HO appear to share mechanobiological pathways, that is, mechanical trauma as a possible cue for soft tissue conversion into hard tissue. Overall, results suggest a systematic well-orchestrated interplay between the metal ion Zn2+ and matrix proteins that incite mineralization of Peyronie’s fibrotic plaque.





5. CONCLUSIONS

Zn, plausibly in the form of trace metal ion Zn2+, was localized at the interface of softer and harder tissues of MPP, indicating the role of Zn-related biochemical pathways in the biomineralization of fibrotic Peyronie’s plaque. Future studies should investigate the phase of mineralized particles, i.e., amorphous or crystalline, in association with the ECM proteins through the use of mechanobiological functional assays. These mechanistic models will reveal the direct influence of shifts in cellular expressions and differentiation. These cellular processes result in a shift in tissue compliance; all of which are necessary to map the biomineralization pathways to mitigate heterotopic mineralization in tissues which otherwise would result in loss of function.
 

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madman

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Figure 1. Mineralized Peyronie’s plaque (MPP) has different mineral densities. (A) Surgically removed MPPs from humans are of different shapes and sizes. (B) 3D rendered volumes of the plaques illustrate regions of distinct mineral densities. A location of 2D virtual section (C) outlined in orange also known as a tomogram is shown in the 3D volume of MPP. (C, D) Lower (blue) mineral density regions surround larger and smaller voids in contrast to higher mineral density regions (red). (E) Box plots illustrate the variation in mineral densities within each specimen (I-XI). (F) An average of lower, higher, and overall mineral densities of MPP are compared with (G) average mineral densities of human skeletal trabecular [26], cortical [26], and alveolar bones [26]. A significant difference between MPP and trabecular bone (p < 0.001) was observed.
Screenshot (9375).png

Screenshot (9376).png
 

madman

Super Moderator
Figure 2. The porosity of MPP decreases with increased mineral density, and MPP contains a tortuous network that changes with the degree of mineralization. (A) Spatial maps of porous networks illustrate pore diameters up to 60 µm. (B) 3D rendered volumes of MPPs illustrate varying morphology and distribution of smaller diameter pores. (C) Box plots illustrate pore diameter and pore volume fractions for lower and higher mineral density regions, and the excised plaque. Significant differences between groups are indicated with *: p < 0.05, **: p < 0.01, and ***: p < 0.001. (D) 3D rendered volumes of X-ray tomograms of MPP illustrate lower to higher mineral density regions of interest (ROI 1-3, green boxes). 2D virtual slices show the location of ROIs 1 (red), 2 (green), and 3 (blue) within the MPP (a). The tortuous network identified in ROI 1 disappeared with increasing mineral density. Regions of lower mineral density contained high pore percentages, and the degree of porosity decreased with an increasing degree of mineralization (b). Distribution of the pore diameter with spline fit within each region (c) and overlap of correlated data between pore diameter and mineral density for the three regions are shown (d).
Screenshot (9377).png

Screenshot (9378).png
 

madman

Super Moderator
Figure 3. Representative structures of lower and higher mineral density regions in Peyronie’s plaque reveal clusters of smaller but electron-dense mineralized particles. (AC) SEM images contain interfaces between higher (asterisk) and lower (arrowhead) mineral density regions of MMP. Red boxes (i-iii) represent the locations of higher-resolution images.
Screenshot (9379).png
 

madman

Super Moderator
Figure 4. MPP consists of regions with varying mineral densities and mineralized particles of different sizes. MPP (A) illustrates a representative 2D XCT tomogram (B) that revealed inherent heterogeneity in mineral density and porosity (C). Various ―clusters of mineralized nodules‖ around cell bodies (i-iii, the locations can be seen in (C)) are shown.
Screenshot (9380).png
 

madman

Super Moderator
Figure 5. Osteocytic lacuna-like regions were contained in higher mineralized regions with Ca and P as elemental composition, and in lower mineralized regions with carbon (C) and nitrogen (N) as the elemental composition. Regions (A-D) illustrate different osteocytic lacuna-like areas within the MPP. These areas consist of varying elemental counts representative of regions that are predominantly organic or inorganic.
Screenshot (9381).png

Screenshot (9382).png
 

madman

Super Moderator
Figure 6. Lower mineral density (MD) regions contain higher zinc (Zn) counts. (A) The location of the 2D virtual section is shown in the 3D-rendered volume. (B) Elemental maps from lower and higher MD regions are shown. (C) Histograms illustrate Zn counts in lower and higher MD regions. Arrowheads (#) and arrows (*) denote lower and higher MD regions, respectively, and also denote areas in the spatial maps in (B).
Screenshot (9383).png
 

madman

Super Moderator
Figure 7. Histology: Osteocytic lacuna-like regions were localized within a higher mineralized collagenous and DMP-1-positive matrix that also is lower in Zn counts. However, this region is surrounded by a softer matrix with higher Zn counts. The presence of blood vessels within these regions was also observed. (A) The 2D virtual section illustrates regions with higher mineral density. (B) H&E illustrates the distribution of cells relative to the matrix. The presence of innervation was detected (black arrow). (C) Gomori trichrome staining illustrates a collagenous matrix in both harder (outlined) and softer regions. (D) Alcian Blue staining reveals the absence of negatively charged proteoglycans in the higher mineralized regions (outlined). (E) Safranin-O counterstained with fast green illustrates the plausible presence of cartilaginous tissues within the higher mineralized regions (outlined). Fast green-positive areas are observed surrounding blood vessels within the outlined regions. The presence of innervation was detected (black arrow). (F) DMP-1 was immunolocalized in higher mineral density regions (outlined). The presence of innervation was detected (black arrow).
Screenshot (9384).png

Screenshot (9385).png
 
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