Despite improvements in surgical techniques, biomechanical constructs, and implants, a proportion of patients still experience the sequelae (chronic shoulder pain and dysfunction) of a nonhealed rotator cuff. Tendon healing typically comprises four components: progenitor cells, growth factors, scaffold, and vascular supply. Unfortunately, tendons have a poor ability to regenerate owing in part to their poor vascular supply. The rotator cuff tendon has limited intrinsic ability to reform all zones of the tendon-to-bone insertion site, as demonstrated by a number of animal studies investigating healing at the tendon-to-bone interface. The zonal insertion site, or enthesis, progresses from tendon to unmineralized fibrocartilage, mineralized fibrocartilage, and bone. Instead, fibrovascular scar tissue rich in type III collagen is produced at the site of healing that is biomechanically weaker than the native structure. It is believed that this weaker product renders repairs prone to subsequent failure.

Using animal models, it is understood that rotator cuff healing occurs in three phases. First, in the inflammatory phase, cytokine-mediated signaling directs macrophages to the site of injury via IGF-1, PDGF, and TGF-β. Macrophages then secrete TGF-β1, commencing the repair phase, which is characterized by fibroblast proliferation and deposition of type III collagen. Finally, the remodeling phase takes place over years and is marked by contraction of the fibrovascular scar tissue mediated by matrix metalloproteinases.

Vitamin D is a fat-soluble vitamin that plays a key role in bone and skeletal muscle metabolism. Low levels of vitamin D are associated with several health issues, including cardiovascular diseases, rickets, and bone fragility followed by stress fractures. The majority of vitamin D is synthesized in the skin by ultraviolet sun radiation to 7-dehydrocholesterol and then hydroxylated by the liver into 25-hydroxvitamin D. This low active form of vitamin D is the most common one circulating in the bloodstream because it has a much greater half-life than the active form 1-25-dihydroxvitamin D and reflects nutritional status as an indicator of vitamin D insufficiency. An enzymatic process in the kidney performs the last hydroxylation to 1-25-dihydroxvitamin D, where it finally receives its hormonal most active form. There is debate regarding the physiologic concentrations specifically, the thresholds for low and high concentrations of vitamin D in the human body. The Institute of Medicine defines a physiologic level of 20 ng/mL, whereas concentrations <12 ng/mL are considered deficient and levels >50 ng/ml may be toxic. In contrast to this classification, several authors have defined four different 25-hydroxvitamin D levels: deficiency is <20 ng/mL; insufficiency is 20–30 ng/mL; sufficiency is >30 to <150 ng/mL; and intoxication is >150 ng/mL.

By definition, matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases that fulfill the task of ECM degradation within various tissues, whereas tissue inhibitors of matrix metalloproteinase (TIMPs) work as endogenous inhibitors to provide a homeostasis by controlling reparative and degradative processes and to maintain a dynamic balance of the ECM. Lately, an imbalance of MMP activity has been associated with degenerative rotator cuff disease. Because the molecular changes occurring in rotator cuff tears are still not completely understood, much attention has been addressed to the role of MMPs in the development of tendinopathy. The MMP family can be subgrouped, with each of them preferring different substrates and sharing similar domain organization. The first group is named collagenases, whose representatives are MMP-1, MMP-8, and MMP-13. They are able to cleave practically all subtypes of collagen, most importantly collagen types I, II, and III. The second group is named gelatinases, consisting of MMP-2 and MMP-9. They degrade smaller collagen fragments as a result of collagenase activity and type IV collagen. Further members are the stromelysins MMP-3, MMP-10, and MMP-11; the matrilysins MMP-7 and MMP-26; and finally the metalloelastase MMP-12 with the capability to primarily degrade glycoproteins and proteoglycans. Subsequently, an additional group of membrane-bound MMPs exist, including MMP-14 and MMP-17, both of which preserve regulatory functions. MMP activity is controlled and regulated by the interaction with the TIMPs numbered from TIMP-1 to TIMP-4. Although they can inhibit all MMPs by a noncovalent interaction with a zinc-binding site in the MMPs, they do not prefer any one individually but are rather ubiquitous. One major MMP function is the control of ECM homeostasis, meaning the regulation of tissue formation and degeneration. The exact process and underlying pathways are not yet fully understood, but it seems that the balance between MMPs and TIMPs plays a crucial role for healing and regeneration, and if it is off balance, it leads to degeneration and rupture. The off-balance shift is usually toward higher MMP concentrations because MMP synthesis can be boosted by various stimuli, including inflammatory cytokines such as IL-1, IL-4, IL-6, or TNF-α. Those cytokines can be detected in chronic and symptomatic cuff pathologies. The overall collagen concentration is reduced over time as an aging process but is significantly altered within degenerative tendon ruptures. Parallel significantly higher protein levels of MMPs can be detected when a tendon rupture is locatable and even differs between full- and partial-thickness defects, pointing out a possible correlation that is so far not completely confirmed. Otherwise, this would imply that MMP activity inhibition with TIMPs or different pharmacologic MMP inhibitors, including tetracycline antibiotics, being probably the most potent MMP inhibitor, might have a beneficial effect. Unfortunately, systematic pharmacologic MMP blocking is associated with a poor healing capacity and tendon quality, as confirmed in several studies. This reveals an important role of MMPs for regenerative processes and cuff healing and demonstrates that MMPs serve as regulators of homeostasis and remodeling agents within intact rotator cuffs with the potential to impair it once overexpressed.