MSC in Tendon and Joint Disease: The Context-Sensitive Link Between Targets and Therapeutic Mechanisms

Abstract

Mesenchymal stromal cells (MSC) represent a promising treatment option for tendon disorders and joint diseases, primarily osteoarthritis. Since MSC are highly context-sensitive to their microenvironment, their therapeutic efficacy is influenced by their tissue-specific pathologically altered targets. These include not only cellular components, such as resident cells and invading immunocompetent cells, but also components of the tissue-characteristic extracellular matrix. Although numerous in vitro models have already shown potential MSC-related mechanisms of action in tendon and joint diseases, only a limited number reflect the disease-specific microenvironment and allow conclusions about well-directed MSC-based therapies for injured tendon and joint-associated tissues. In both injured tissue types, inflammatory processes play a pivotal pathophysiological role. In this context, MSC-mediated macrophage modulation seems to be an important mode of action across these tissues. Additional target cells of MSC applied in tendon and joint disorders include tenocytes, synoviocytes as well as other invading and resident immune cells. It remains of critical importance whether the context-sensitive interplay between MSC and tissue- and disease-specific targets results in an overall promotion or inhibition of the desired therapeutic effects. This review presents the authors’ viewpoint on disease-related targets of MSC therapeutically applied in tendon and joint diseases, focusing on the equine patient as valid animal model.

Differential Smad2/3 linker phosphorylation is a crosstalk mechanism of Rho/ROCK and canonical TGF-β3 signaling in tenogenic differentiation

“…The Smad signaling pathway is the canonical transduction pathway downstream of TGF-β receptors, resulting in nuclear translocation of a Smad complex to modulate gene expression 22 . However, MSC act in a highly context-dependent manner and can alter their TGF-β response depending on other environmental stimuli 23 . Therefore, it is necessary to understand the crosstalk between Smad and other, especially mechanosensitive, signaling pathways.…”

Systematic review and meta-analysis of positive long-term effects after intra-articular administration of orthobiologic therapeutics in horses with naturally occurring osteoarthritis

“…The characteristic differentiation potential of these cells has laid the foundation to prove therapeutic concepts in various fields of medicine where tissue regeneration and restoration are the aimed effects (44)(45)(46)(47)(48)(49). In the process of clinical stem cell application, orthopedic diseases such as OA were becoming an inherent part of scientific interest (35,50). The common term "stem cell" is nowadays used in popular science and increasingly replaced by the more scientific expression of a "multipotent mesenchymal stromal cell (MSC)" because specific stem cell characteristics (51) [long in vivo survivability, ability for self-replication and multipotent differentiation into certain tissue types (43)] are insufficiently accurate to prove in therapeutic purposes.…”

“…Beneficial clinical effects described after an intra-articular administration of biological therapeutics include reduction of lameness and joint effusion (30)(31)(32). It is assumed that clinically relevant effects of intra-articular administered blood products and MSCs in OA-affected joints in part are attributed to locally effective growth factors, cytokines, as well as secretomes and exosomes from delivered cells, which further innate on-site cell regeneration (33)(34)(35). Although the group of these so named orthobiologics or orthobiologic therapeutic agents is not totally consistent due to differences in manufacturing, processing and application, they all share potential regenerative effects on the described articular tissues proven in vitro (26,36,37) and in vivo (38-40) studies.…”