Effects of intra-articular applied rat BMSCs expressing alpha-calcitonin gene-related peptide or substance P on osteoarthritis pathogenesis in a murine surgical osteoarthritis model.

Background: About 655 million persons worldwide are affected by osteoarthritis (OA). As no therapy modifies disease progression long-term, there is an immense clinical need for novel therapies. The joints are innervated by alpha calcitonin gene-related peptide (αCGRP)- and substance P (SP)-positive sensory nerve fibers. Both neuropeptides have trophic effects on target cells within the joints. The aim of this study was to examine the effects of SP- and αCGRP-expressing intra-articular (i.a.) applied rat(r)BMSC on cartilage and subchondral bone structural changes after OA induction.

Methods: Mice were subjected to destabilization of the medial meniscus (DMM) surgery, followed by i.a. injections with rBMSC, transduced with lacZ, SP or αCGRP. 2, 8 and 16 weeks after DMM/Sham surgery, motion analysis and serum marker analysis were performed. Cartilage and subchondral bone properties were assessed by OA scoring, atomic force microscopy and nano-CT analysis.

Results: OARSI scores of the medial cartilage compartments indicated induction and progression of OA after DMM surgery in all groups. Differences between the treatment groups were mostly restricted to the lateral cartilage compartments, where αCGRP caused a decrease of structural changes. DMM-rBMSC-αCGRP or -SP mice displayed decreased cartilage stiffness in the cartilage middle zone. DMM-rBMSC-αCGRP mice revealed improved mobility, whereas Sham-rBMSC-SP mice revealed reduced mobility compared to rBMSC-lacZ. With respect to condyle length, subarticular bone and ephiphyseal bone morphology, DMM-rBMSC-SP mice had more alterations indicating either a more progressed OA stage or a more severe OA pathology compared to controls. In addition, DMM-rBMSC-SP mice developed osteophytes already 8 weeks after surgery. Adiponectin serum level was increased in DMM-rBMSC-αCGRP mice, and MIP1b level in DMM-rBMSC-SP mice. Notably, pain and inflammation markers increased over time in rBMSC-SP mice while rBMSC-αCGRP mice revealed a bell-shaped curve with a peak at 8 weeks.

Conclusions: We conclude that i.a. injection of rBMSC in general have a beneficial effect on cartilage matrix structure, subchondral bone microarchitecture and inflammation. rBMSC-αCGRP have anabolic and possible analgesic properties and may attenuate the progression or severity of OA. In contrast, rBMSC-SP exert a more catabolic influence on knee joints of both, Sham and DMM mice, making it a potential candidate for inhibition studies.