Once believed to be limited to articular cartilage, osteoarthritis is now considered to be an organ disease of the “whole joint.” Damage to the articular surface can lead to, be caused by, or occur in parallel with, damage to other tissues in the joint. The relationship between cartilage and the underlying subchondral bone has particular importance when assessing joint health and determining treatment strategies. The articular cartilage is anchored to the subchondral bone through an interface of calcified cartilage, which as a whole makes up the osteochondral unit. This unit functions primarily by transferring load-bearing weight over the joint to allow for normal joint articulation and movement. Unfortunately, irreversible damage and degeneration of the osteochondral unit can severely limit joint function. Our understanding of joint pain, the primary complaint of patients, is poorly understood and past efforts toward structural cartilage restoration have often not been associated with a reduction in pain. Continued research focusing on the contribution of subchondral bone and restoration of the entire osteochondral unit are therefore needed, with the hope that this will lead to curative, and not merely palliative, treatment options. The purpose of this narrative review is to investigate the role of the osteochondral unit in joint health and disease. Topics of discussion include the crosstalk between cartilage and bone, the efficacy of diagnostic procedures, the origins of joint pain, current and emerging treatment paradigms, and suitable preclinical animal models for safety and efficacy assessment of novel osteochondral therapies. The goal of the review is to facilitate an appreciation of the important role played by the subchondral bone in joint pain and why the osteochondral unit as a whole should be considered in many cases of joint restoration strategies. Impact Statement In this comprehensive review, we are providing a holistic overview of osteochondral tissue development, disease, pain localization, as well as structural evaluation and current repair strategies. This review is intended to serve as a broad introduction to this multidisciplinary research area. It is a thorough examination of the biological aspects of the osteochondral unit from a tissue engineering perspective, highlighting the importance of the subchondral bone in chondral and osteochondral lesion repair and pain relief.

Ro 21-7634 was examined for oral antiallergic activity in two in vivo models commonly used to evaluate antiallergics. In the rat PCA test, this drug had an oral ID50 of 1.14 mg/kg and was found to be more potent than several other antiallergics including Disodium Cromoglycate (cromoglycate), Oxatomide, Doxanthrazole, Xanoxate, 2,6-bis (ethyoxyoxalylamino) pyridine, PRD-92-EA and M + B 22,948. In contrast to cromoglycate, Ro 21-7634 was found to be an orally active inhibitor of antigen-induced broncho-constriction in passively sensitized rats (ID50 = 0.2 mg/kg). In addition, Ro 21-7634 inhibited antigen-induced histamine release in an in vivo passive peritoneal anaphylaxis test system, following intraperitoneal administration. Ro 21-7634 demonstrated no end organ antagonism toward histamine, metacholine or serotonin in the guinea pig.

Chemotherapy can cause early menopause or infertility in women and have a profound negative impact on the quality of life of young female cancer survivors. Various factors are known to influence the risk of chemotherapy-induced ovarian failure, including the drug dose and treatment duration; however, the scheduling of dose administration has not yet been evaluated as an independent risk factor. We hypothesized that low-dose metronomic (LDM) chemotherapy scheduling would be less detrimental to ovarian function than the traditional maximum tolerated dose (MTD) strategy. In vitro, MTD cyclophosphamide exposure resulted in decreased proliferation and increased granulosa cell apoptosis, while cells treated with LDM cyclophosphamide were not different from untreated controls. Treatments of MTD cyclophosphamide induced high levels of follicle atresia and enhanced follicle recruitment in mice. In contrast, LDM delivery of an equivalent dose of cyclophosphamide reduced growing follicle numbers, but was not associated with higher levels of follicle atresia or recruitment. MTD cyclophosphamide induced significant vascular disruption and DNA damage in vivo, while LDM chemotherapy with equal cumulative amounts of cyclophosphamide was not different from controls. MTD chemotherapy also had a negative effect on mouse-fertility outcomes. Our findings suggest that LDM scheduling could potentially minimize the long-term effects of cyclophosphamide on female fertility by preventing follicle depletion from enhanced activation.

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