Parathyroid hormone enhances the therapeutic effect of mesenchymal stem cells on temporomandibular joint osteoarthritis in rats.

Am J Stem Cells 2023;12(4):73-82 www.AJSC.us /ISSN:2160-4150/AJSC0151698 Original Article Parathyroid hormone enhances the therapeutic effect of mesenchymal stem cells on temporomandibular joint osteoarthritis in rats Haitao Jiang1*, Qiuyu Tang2*, Dexin Zheng1, Yunkai Gu3, Cheng Man1 Department of Oral and Maxillofacial Trauma and Orthognathic Surgery, Stomatological Hospital of Zunyi Medical University, Zunyi, Guizhou, China; 2Honghuagang District Stomatological Hospital of Zunyi City, Zunyi, Guizhou, China; 3Department of Stomatology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China. * Equal contributors. 1 Received June 10, 2023; Accepted September 12, 2023; Epub October 20, 2023; Published October 30, 2023 Abstract: Objectives: Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease affecting the joint, which is characterized by injury to the articular cartilage, as well as changes in the synovial and subchondral bone. TMJOA has a high incidence rate, without any effective treatment. Despite the therapeutic potential of mesenchymal stem cells (MSCs) in various diseases, their efficacy in treating TMJOA is constrained by the local hypoxic conditions and elevated reactive oxygen species (ROS) environment within the damaged temporomandibular joint. In recent years, many studies have reported that parathyroid hormone (PTH) can effectively treat TMJOA, and has an important impact on MSC differentiation. Therefore, we hypothesized that PTH may influence the potential of MSCs, thereby improving their therapeutic effect on TMJOA. Methods: First, we isolated and cultured rat bone marrow MSCs, and evaluated their proliferation and differentiation after adding PTH. Next, the in vitro environment of hypoxia and high ROS was established by hypoxia condition and H2O2 treatment, and the resistance of PTH-treated MSCs to hypoxia and ROS was subsequently investigated. Finally, PTH-treated MSCs were used to treat TMJOA in a rat model to evaluate the efficacy of PTH. Results: PTH enhanced the proliferation ability of MSCs, promoted the osteogenic differentiation of MSCs, and improved the tolerance of MSCs to hypoxia and ROS. Finally, the therapeutic effect of PTH-treated MSCs on TMJOA was significantly improved. Conclusion: PTH enhances the therapeutic effect of MSCs on TMJOA in rats. Keywords: Temporomandibuar joint osteoarthritis, parathyroid hormone, mesenchymal stem cells, homing, repair, proliferation and differentiation ability Introduction Temporomandibular joint osteoarthritis (TMJOA) is distinguished by articular cartilage injury, along with synovial and subchondral bone alterations. The prevalence of TMJOA is 18.2742.9% in China, and it can lead to maxillofacial pain and movement impairments, thereby imposing a significant psychological and physiological burden on affected individuals [1]. The etiology and progression of TMJOA involve complex mechanisms such as tissue damage and inflammation, which makes the treatment more challenging. Currently, clinical management of TMJOA primarily focuses on disease progression control, pain reduction, drug therapy, phys- ical therapy, and inflammation control. However, there is a lack of pharmacological interventions and methodologies that can effectively manage the progression of TMJOA [2]. In recent years, the study of stem cells, particularly mesenchymal stem cells (MSCs), has presented new hope for the treatment of many diseases. Compared to traditional treatment methods, it offers several distinct advantages. First, MSCs have the ability to home in on the site of injury and subsequently differentiate into specific tissue cells, facilitating repair of the injured area. Second, MSCs can secrete cytokines that promote damage repair and regulate the local inflammatory response, thereby reduc- PTH promotes therapy of MSC on TMJOA ing the “inflammatory pressure” and preserving homeostasis in the microenvironment [3, 4]. Given the therapeutic effects of MSCs on other diseases, some researchers investigated its potential application in treating osteoarthrosis (OA) but with limited success [5]. The reason for this is that the temporomandibular joint is relatively small compared to larger joints, resulting in inadequate blood and oxygen supply. When inflammatory injuries occur, oxygen supply becomes even more challenging, leading to the inhibition of proliferation and differentiation of transplanted MSCs in the damaged temporomandibular joint cavity [6]. Therefore, how to improve the proliferation and differentiation ability of MSCs in the temporomandibular joint cavity has become a research hotspot. Parathyroid hormone (PTH) is an alkaline single-chain polypeptide hormone secreted by parathyroid cells. Its primary function is to regulate the metabolism of calcium and phosphorus in vertebrates, promoting an increase in blood calcium levels and a decrease in blood phosphorus levels. Hence, it plays a vital role in bone development and formation. PTH (1-34) is currently the only anabolic drug approved by the US Food and Drug Administration (FDA) for the treatment of osteoporosis [7]. Jun Zhang et al. proved that PTH can effectively treat TMJOA, especially degenerative temporomandibular arthritis [8]. Studies have shown that PTH can regulate the differentiation of MSCs in vitro, as well as expand the number of MSCs, indicating that PTH can promote the proliferation and osteogenic differentiation of MSCs [9]. Based on the above role of PTH in bone development and MSC regulation, we hypothesized that PTH may enhance the therapeutic effect of MSCs on TMJOA. In this study, we explored the effect of PTH-treated MSCs on TMJOA, and the results showed that PTH significantly enhanced the proliferation of MSCs and increased their tolerance to ROS and hypoxia, ultimately enhancing the therapeutic effect of MSCs on TMJOA. Methods Experimental animals Ninety 8-week-old female Wistar rats weighing approximately 200 g were purchased from the SPF rat feeding center at Zunyi Medical University’s Experimental Animal Center. The 74 rats underwent adaptive feeding for one week at the Laboratory of Experimental Animal Center at Zunyi Medical University, and were provided with free access to food and drinking water. The rats remained in good health throughout the study, with no instances of death. All subsequent experimental procedures were conducted in accordance with the ethical standards for animal research. To minimize the discomfort to rats, all operations were performed under anesthesia. Experimental reagents Sodium iodoacetate (MIA) was purchased from MERCK (No. 57858, Merck KGaA, Darmstadt, Germany). Parathyroid hormone (1-34) (rat) acetate [PTH (1-34)] was purchased from MCE (No. HY-P2279A, New Jersey, USA). The CCK8 assay kit was purchased from Dongren Chemical Technology (Shanghai) Co., Ltd. (No. CK04, Shanghai, China). The EdU assay kit was purchased from Beyotime Biotechnology (No. C0071S, Shanghai, China). The (...truncated)