Osteolysis of the distal phalanges of the hands and feet can affect the terminal tuft or the shaft of the distal phalanx. Digital acro-osteolysis can result from ischemia, digital calcinosis, or severe sensory neuropathy. Acro-osteolysis is associated with occupational activities, such as exposure to polyvinyl chloride, infections such as leprosy, endocrinopathies such as hyperparathyroidism, genetic disorders, lysosomal storage disorders, and rheumatic diseases, such as systemic sclerosis (SSc), which is an autoimmune disease characterized by progressive vasculopathy with resultant fibrosis [1]. Unfortunately, there is a paucity of data on the effective treatment of acro-osteolysis, especially in the context of recurrent ischemia-reperfusion injury, which is important for the pathogenesis of SSc [2].
It is of critical importance in SSc to identify when a digital tip is at risk of resorption prior to end-stage damage. Severe Raynaud’s phenomenon (RP), which is a vasospasm in the digits that is universally present in SSc, can result in digital complications, such as calcinosis, digital ischemia, and acro-osteolysis. The presence of calcinosis and digital ischemia have been reported to predict acro-osteolysis [2]. Vasodilators have been prescribed for the management of RP. Acro-osteolysis is the likely result of bone damage due to inadequate vasodilator response or sub-optimally treated vasculopathy. However, acro-osteolysis can occur despite pharmacologically controlled symptomatic RP, highlighting the importance of biomarkers for identifying acro-osteolysis [4]. The extraarticular location and lack of inflammation suggest that the mechanism underlying SSc-related acro-osteolysis may be hypoxia generated and pathologic bone remodeling [3]. Longitudinal studies assessing prognostic factors and predictors of SSc-acro-osteolysis are needed [2].
Plain radiography of the hands is the gold standard for the detection of acro-osteolysis, which is most often reported as present or absent, as none of the existing radiographic scales to grade osteolysis have been validated [2]. Ultrasonography is more sensitive for the detection of acro-osteolysis in patients with SSc. An increased Doppler signal adjacent to acro-osteolytic lesions in SSc may reflect the active process of osteogenesis [5]. In response to damage, bone remodeling requires coordinated activity of bone-forming osteoblasts and bone-resorbing osteoclasts to maintain bone mass and strength. Bone turnover markers, which are protein derivative biomarkers released during bone remodeling by osteoblasts or osteoclasts, are used as an adjunct for osteoporosis diagnosis and therapeutic monitoring and have been reported in SSc when compared to controls.[6] However, earlier menopause, corticosteroid use, malabsorption, and inflammation may be confounders in studies using bone turnover markers in SSc [7]. Therefore, predictive biomarkers that capture vascular and bone pathogenesis in ischemic digital lesions are needed [8].
There is increasing preclinical evidence that heparin/endothelial glycocalyx-binding molecule midkine (MK) plays a pathological role in hypertension, vascular disease, and bone pathology [9]. Although MK gene expression is generally weak in physiological homeostasis, it is strongly induced during acute oxidative stress, inflammation, and tissue repair [10]. Inflammatory cell recruitment by MK causes a variety of pathological changes, and blood levels of MK are reported to be potentially helpful markers of pathological disease activity [11]. MK may play an adaptive role in acute ischemia versus chronic disease states [9] and is considered an angiogenic growth factor that plays a key role in bone remodeling as a negative modulator of osteoblast function, and it is expressed during fracture repair [12]. Evidence suggests that MK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression, suggesting that the MK-modulated microenvironment is critically important for determining levels [13]. The objective of this study was to examine whether the serum MK level is a biomarker associated with acro-osteolysis in SSc.