Calcium Hydroxylapatite Injection Improves Senile Purpura via <scp>YAP</scp> ‐Mediated Mechanotransduction

Senile purpura is characterized by the recurrent ecchymoses following minor trauma [1]. This condition arises due to the weakening of the structural integrity of dermal collagenous tissues and increased fragility of blood vessels. Therapeutic approaches that restore the structural support of the dermal extracellular matrix (ECM) in patients with senile purpura may lead to progressive improvements. Calcium hydroxylapatite (CaHA) has been used as a dermal filler and is known to improve skin quality by inducing mechanotransduction, a process in which mechanical stimuli are converted into biochemical signals [2]. The transcriptional regulator YAP has been highlighted as a key cellular mechanotransducer that exerts influence over collagen synthesis and skin regeneration [3]. A 65-year-old male and a 67-year-old male presented with recurrent bruises on the dorsum of hands (Figure 1a). Despite the regular use of moisturizers and physical protection, purpura continued to worsen. Consequently, 1.5 cc of CaHA (Radiesse; Merz, Raleigh, NC) was diluted in a 1:1 ratio with 0.1% lidocaine and injected subdermally into the dorsum of the hand using a proximal-to-distal fanning technique. The injection was performed on the left hand at baseline, while the right hand remained untreated to serve as a comparison control. After 3 months, gross examination revealed clinical improvements in senile purpura, skin texture, and volume, compared to the baseline (Figure 1a,b). Two punch biopsy specimens were obtained for histopathological examination. The treated side tended to have greater epidermal thickness compared to the control side. Additionally, special stains demonstrated more prominent collagen and elastic fibers in the treated area (Figure 1c–e). Immunohistochemistry analysis also revealed the number of cells exhibiting increased YAP expression after the treatment (Figure 1f,h). The expression of vascular endothelial growth factor is higher in the treated side compared to the control (Figure 1g,i). Given that YAP regulates collagen production in fibroblasts and mediates feedback mechanisms in cellular mechanotransduction, these findings suggest that ECM synthesis following CaHA treatment occurs via a mechanotransduction pathway involving YAP activation. In both patients, CaHA was also administered to the control hand at 3 months, with follow-up for another 3 months post-procedure. Both hands demonstrated sustained improvement in hand volume and skin quality, with favorable clinical results up to 6 months. To address whether CaHA modulates the YAP-mediated mechanotransduction pathway, we performed a 3-dimensional spheroid culture experiment using benign immortalized human dermal fibroblasts and retinal pigment epithelium-1 (RPE1) cells (Supplementary Text, available via Mendeley at https://doi.org/10.17632/b2j2rdxv5n.1), more relevant to the in vivo condition (Figure 2 and Supplementary Figure 1) [4]. Cells exhibiting high levels of nuclear YAP enrichment, indicative of YAP activation, were more frequent in the condition where CaHA was supplemented, compared to the control (Figure 2b,c). Fibroblasts adhering to CaHA microspheres exhibited actin cytoskeletal remodeling (Figure 2c), which is known to strongly influence YAP activity. Our study shows that injecting diluted CaHA into the dorsum of the hand improves senile purpura, accompanied by histological evidence of epidermal and dermal proliferation, increased collagen and elastic fiber density. This dermal ECM reinforcement likely stabilizes fragile vasculature [3]. Notably, we observed a significant increase in YAP-positive cells in the dermis post-CaHA injection, supported by in vitro spheroid culture. Since YAP regulates ECM homeostasis and is suppressed in aged fibroblasts due to reduced mechanical cues, CaHA may restore dermal stiffness and activate YAP-dependent mechanotransduction, promoting neocollagenesis and skin integrity [5]. Nevertheless, this study represents a preliminary and exploratory observation intended to stimulate further controlled trials. Moreover, the clinical inference of our findings is limited by the sample size, male sex homogeneity, and a short follow-up period. While further studies are required to determine whether CaHA can provide long-term improvement for senile purpura, its use may be considered a treatment option for patients unresponsive to conservative therapies. This study was supported by a research grant from Merz Asia Pacific Pte. Ltd. The patient provided written informed consent for the use of clinical images and related data for research and publication purposes. The authors declare no conflicts of interest. The data that supports the findings of this study are available in the supporting information of this article.