Orthodontics, which relies on active periodontal tissue remodeling to move teeth, has always faced challenges in maintaining retention after treatment. The stability of orthodontic retention is influenced by various factors, among which the impact of fibrous tissue is key, particularly in twisted teeth. Current evidence does not indicate that any specific fiber composition dominates the drive to recurrence (Recurrence means moved teeth returned to their original position); however, there have been reported that collagen fibers, or myofibroblasts, may stimulate recurrence (Meng et al., 2018, Meng et al., 2019). In previous studies, use of relaxin to inhibit fiber formation effectively reduced the recurrence of both rotated teeth and mesial molar movement (Liu et al., 2005, Stewart et al., 2005); however, relaxin also has an indirect activation effect on bone through transformation osteogenic and osteoclast differentiation. Given these limitations of relaxin, it is necessary to identify drugs that can inhibit the production of fibrous matrix and ameliorate the effects of fiber stress, without affecting bone mineralization.

Hyaluronic acid (HA) is an important component of the extracellular matrix, widely present in the skin, synovial joints, and periodontal tissues (Rabasseda, 2000). High molecular weight HA can prevent intercellular contact, fill intercellular spaces, lubricate tissues, and alleviate inflammation. HA can also be transformed into low molecular weight forms, which have roles in cytokine signaling and contribute to regulation of inflammation (Petrey and de la Motte, 2014). HA expression levels are significantly increased when periodontitis occurs or orthodontic treatment is applied (Sato et al., 2010). In skin fibroblasts, TGF-β induces myofibroblast transformation and collagen synthesis, which require the involvement of low molecular weight HA binding and CD44 signaling (Suleiman et al., 2018); hence, inhibiting HA synthesis can reverse myofibroblast transformation. In previous studies, tooth movement was accompanied by a significant increase in TGF-β in the compressed and stretched areas of the periodontal ligament. In addition to being associated with bone metabolism pathways (Jeon et al., 2021), this upward trend may also be closely related to HA production. Therefore, clearing of HA can be predicted to reverse excessive collagen production and high tension on myofibroblasts in periodontal fibrous tissue under inflammatory condition (Petrey and de la Motte, 2014).

Hyaluronidase (HYAL) can alter tissue structure by dissolving HA, increasing its diffusion characteristics, generating HA of different chain lengths, and stimulating new biochemical reactions by changing binding of HA (Weber et al., 2019). The functions of HYAL in this context include inhibiting myofibroblast phenotype maintenance and inflammation progression (Rezvani et al., 2020), as well as promoting angiogenesis (Cowman, 2017). In clinical practice, HYAL injection can also reduce tissue scar (Kakar et al., 1985), increase tissue compliance and plasticity (Byers et al., 2010), and reduce the stress generated by fibrous tissue (Weber et al., 2019). Whether HYAL can inhibit fiber proliferation under inflammatory conditions, the specific components of inhibitory fibers, and their impacts on periodontal bone mass are yet to be determined. Some orthodontics scholars have proposed that, when periodontal ligament tissue is subjected to tensile stress, fibroblasts undergo myofibroblast transformation to resist stress changes, increase tissue contraction force, and express the characteristic marker, actin alpha 2, smooth muscle (ACTA2) (Jung et al., 2013, Xu et al., 2015). These authors also proposed that this transformation can cause fiber-induced recurrence. Further, collagen accumulation and increase are considered a factor underlying recurrent tooth movement (Tuncay and Killiany, 1986). After orthodontic movement, collagen and fibronectin molecules are crucial in tissue remodeling (Bumann et al., 1997). Despite the stress relaxation and viscoelastic behavior of collagen fibers (Li et al., 2020), relatively long reconstruction period may be an inevitable obstacle to retention (Meng et al., 2018).

In this study, we treated rat periodontal ligament cells (rPDLCs) with HYAL, to explore whether it can inhibit collagen fiber generation and ACTA2 production, with the aim of determining potential methods to ameliorate the stress generated by periodontal fibrous tissue and reduce the degree of recurrence without decreasing bone mineralization.