Evans, Christopher H.

ABSTRACT Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single‐chain (sc) IL‐23 (Ad.scIL‐23) was able to induce systemic antitumor immunity. Here, we examined the role of IL‐23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL‐23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL‐23–treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL‐17–producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti–IL‐17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL‐23–treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.—Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single‐chain IL‐23 induces psoriatic arthritis–like symptoms in NOD mice. FASEB J. 33, 9505–9515 (2019). www.fasebj.org

ABSTRACT Regenerative rehabilitation is an emerging area of investigation that seeks to integrate regenerative medicine with rehabilitation medicine. It is based on the realization that combining these two areas of medicine at an early stage of treatment will produce a better clinical outcome than the traditional linear approach of first administering the elements of regeneration followed, after a delay, by rehabilitation. Indeed, in certain settings, a case can be made for initiating rehabilitation protocols before starting regenerative intervention. This review summarizes the contents of a workshop held during the 2018 annual meeting of the Orthopaedic Research Society. It introduced the concept of regenerative rehabilitation and then provided two orthopaedic examples drawn from the domains of cartilage repair and bone healing. Rehabilitation medicine can supply a variety of physical stimuli, including electrical stimulation, thermal stimulation and mechanical stimulation. Of these, mechanical stimulation has the most obvious relevance to orthopaedics. The mechano‐responsiveness of cartilage and bone has been known for a long time, but is poorly understood and has led to only limited clinical application. Improved bioreactor designs that allow multi‐axial loading enable new insights into the responsiveness of chondrocytes and chondroprogenitor cells to specific types of load, especially shear. Recent studies on the mechanobiology of bone healing show that modulating the mechanical environment of an experimental osseous lesion by a process of “Reverse Dynamization” soon after injury considerably enhances healing. Future studies are needed to probe the molecular mechanisms responsible for these phenomena and to translate these findings into clinical practice. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1263–1269, 2019.

Background: The paratenon is important for Achilles tendon healing. There is much interest in the use of exogenous growth factors (GFs) as potential agents for accelerating the healing of damaged Achilles tendons. Purpose/Hypothesis: The present study used a rat model to study the responses of the injured Achilles tendon to GFs in the presence or absence of the paratenon. The hypothesis was that responses of the injured tendon to GFs would be lower in the absence of a paratenon. Study Design: Controlled laboratory study. Methods: A 4-mm defect was created in the right Achilles tendon of 60 skeletally mature rats, which were treated with a validated combination of GFs (bFGF, BMP-12, and TGF-β1). Animals were randomly assigned to the intact paratenon (IP) group or resected paratenon (RP) group. Healing was studied anatomically, mechanically, and histologically after 1, 2, and 4 weeks. Results: IP tendons showed improved healing compared with RP tendons. IP tendons were significantly stronger (32.2 N and 48.9 N, respectively) than RP tendons (20.1 N and 31.1 N, respectively) after 1 and 2 weeks. IP tendons did not elongate as much as RP tendons and had greater cross-sectional areas (18.0 mm 2 , 14.4 mm 2 , and 16.4 mm 2 , respectively) after 1, 2, and 4 weeks compared with RP tendons (10.5 mm 2 , 8.4 mm 2 , and 11.9 mm 2 , respectively). On histology, earlier collagen deposition and parallel orientation of fibrils were found for IP tendons. Conclusion: The paratenon is essential for efficient Achilles tendon healing. Healing with GFs in this Achilles tendon defect model was superior in the presence of the paratenon. Clinical Relevance: Biological approaches to tendon engineering using GFs are in vogue and have been shown to improve healing of the rat Achilles tendon, most likely by inducing progenitor cells located within the paratenon. Clinically, resection or incision of the paratenon has been proposed for wound closure. Our data demonstrate the fundamental importance of the paratenon, which therefore should be preserved during Achilles tendon repair, especially if augmented with products such as platelet-rich plasma or autologous conditioned serum that are rich in GFs.

An innovative strategy for delivering drugs to chondrocytes in situ offers new avenues for treating osteoarthritis (Geiger et al ., this issue).