Frozen Shoulder: A Systematic Review of Cellular, Molecular, and Metabolic Findings

Abstract

Frozen shoulder is a common, poorly understood condition affecting the shoulder joint, with poor long-term outcomes in some in relation to pain and mobility. Understanding the pathophysiology of frozen shoulder at a cellular level and a molecular level may help in the development of novel treatments. The aim of this study was to perform a systematic review of studies examining the cellular, molecular, and metabolic findings in frozen shoulder. A literature search was conducted using Embase, CINAHL (Cumulative Index of Nursing and Allied Health Literature), and PubMed using relevant terms. Studies were included if they assessed cellular, molecular, or metabolic alterations in tissue or blood samples of patients with frozen shoulder. Of 4,794 studies identified, 25 were included for analysis. Histological findings included nonspecific chronic inflammation and the proliferation of fibroblasts, adipocytes, and blood vessels. Molecular studies showed increased pro-inflammatory mediators, reduced matrix metalloproteinases (MMPs), and increased activity of factors promoting fibroblast activation and nerve growth. Metabolic alterations included an increase in blood lipids. Frozen shoulder is thought to occur after a primary insult to the shoulder triggers a complex cascade and upregulation of growth factors and cytokines with an increased turnover of the extracellular matrix, activation of myofibroblasts with deposition of collagen, and reduced matrix degradation. The presence of a background pro-inflammatory state (e.g., patients with diabetes or hyperlipidemia) may exacerbate these abnormalities. Further work assessing patients in early stages of the disease and comparing the inflammatory or fibrogenic characteristics of the shoulder capsule with those of the other joints may help to determine the initiating factors and to explain the predisposition of the shoulder to stiffness. Our findings may form the basis for identifying new targets for the clinical management of frozen shoulder. [Abstract copyright: Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.]