Osteoarthritis (OA) is a progressive and disabling musculoskeletal disease affecting millions of people and resulting in major healthcare costs worldwide. It is the most common form of arthritis, characterised by degradation of the articular cartilage, formation of osteophytes, subchondral sclerosis, synovial inflammation and ultimate loss of joint function. Understanding the pathogenesis of OA and its multifactorial aetiology will lead to the development of effective treatments, which are currently lacking. Two-dimensional (2D) in vitro tissue models of OA allow affordable, high-throughput analysis and stringent control over specific variables. However, they are linear in fashion and are not representative of physiological conditions. Recent in vitro studies have adopted three-dimensional (3D) tissue models of OA, which retain the advantages of 2D models and are able to mimic physiological conditions, thereby allowing investigation of additional variables including interactions between the cells and their surrounding extracellular matrix. Numerous spontaneous and induced animal models are used to reproduce the onset and monitor the progression of OA based on the aetiology under investigation. This therefore allows elucidation of the pathogenesis of OA and will ultimately enable the development of novel and specific therapeutic interventions. This review summarises the current understanding of in vitro and in vivo OA models in the context of disease pathophysiology, classification and relevance, thus providing new insights and directions for OA research.

Compared with our understanding of endochondral ossification, much less is known about the coordinated arrest of growth defined by the narrowing and fusion of the cartilaginous growth plate. Throughout the musculoskeletal system, appropriate cell and tissue responses to mechanical force delineate morphogenesis and ensure lifelong health. It remains unclear how mechanical cues are integrated into many biological programs, including those coordinating the ossification of the adolescent growth plate at the cessation of growth. Primary cilia are microtubule-based organelles tuning a range of cell activities, including signaling cascades activated or modulated by extracellular biophysical cues. Cilia have been proposed to directly facilitate cell mechanotransduction. To explore the influence of primary cilia in the mouse adolescent limb, we conditionally targeted the ciliary gene Intraflagellar transport protein 88 (Ift88 fl/fl ) in the juvenile and adolescent skeleton using a cartilage-specific, inducible Cre (AggrecanCreER T2 Ift88 fl/fl ). Deletion of IFT88 in cartilage, which reduced ciliation in the growth plate, disrupted chondrocyte differentiation, cartilage resorption, and mineralization. These effects were largely restricted to peripheral tibial regions beneath the load-bearing compartments of the knee. These regions were typified by an enlarged population of hypertrophic chondrocytes. Although normal patterns of hedgehog signaling were maintained, targeting IFT88 inhibited hypertrophic chondrocyte VEGF expression and downstream vascular recruitment, osteoclastic activity, and the replacement of cartilage with bone. In control mice, increases to physiological loading also impair ossification in the peripheral growth plate, mimicking the effects of IFT88 deletion. Limb immobilization inhibited changes to VEGF expression and epiphyseal morphology in Ift88cKO mice, indicating the effects of depletion of IFT88 in the adolescent growth plate are mechano-dependent. We propose that during this pivotal phase in adolescent skeletal maturation, ciliary IFT88 protects uniform, coordinated ossification of the growth plate from an otherwise disruptive heterogeneity of physiological mechanical forces.

Summary Objective To examine the relationship between height gain across childhood and adolescence with knee osteoarthritis in the MRC National Survey of Health and Development (NSHD). Materials and methods Data are from 3035 male and female participants of the NSHD. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at ages 20 years. Associations between (1) height at each age (2) height gain during specific life periods (3) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and knee osteoarthritis at 53 years were tested. Results In sex-adjusted models, estimated associations between taller height and decreased odds of knee osteoarthritis at age 53 years were small at all ages - the largest associations were an OR of knee osteoarthritis of 0.9 per 5 cm increase in height at age 4, (95% CI 0.7–1.1) and an OR of 0.9 per 5 cm increase in height, (95% CI 0.8–1.0) at age 6. No associations were found between height gain during specific life periods or the SITAR growth curve variables and odds of knee osteoarthritis. Conclusions There was limited evidence to suggest that taller height in childhood is associated with decreased odds of knee osteoarthritis at age 53 years in this cohort. This work enhances our understanding of osteoarthritis predisposition and the contribution of life course height to this.

Objectives To examine the relationship between height gain across childhood and adolescence with knee osteoarthritis in the MRC National Survey of Health and Development (NSHD). Methods Data are from 3035 male and female participants of the NSHD. Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at ages 20 and 26 years. Associations between (i) height at each age (ii) height gain during specific life periods (iii) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity, and knee osteoarthritis at 53 years were tested. Results In sex-adjusted models, taller height at 4 and 6 years were modestly associated with decreased odds of knee osteoarthritis at age 53 (ORs per 1cm increase in height at age 6: 0.97 and age 4: 0.98 (95% CI: 0.95-1.00)). These associations were attenuated after adjustment for potential confounders. Similarly, taller adult achieved height measured at 26 and 53 years of age were associated with decreased odds of knee osteoarthritis (OR per 1cm increase in height: 0.98 (95% CI 0.96 to 1.00)). No associations were found between height gain during specific life periods or the SITAR growth curve variables and odds of knee osteoarthritis. Conclusions There was some limited evidence to suggest that taller height in childhood is associated with decreased odds of knee osteoarthritis at age 53 years in this cohort. This work enhances our understanding of osteoarthritis predisposition and the contribution of life course height to this.

Aims Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 ( Socs2 -/-) display accelerated bone growth. Methods We examined vulnerability of Socs2 -/- mice to OA following surgical induction of disease (destabilization of the medial meniscus (DMM)), and with ageing, by histology and micro-CT. Results We observed a significant increase in mean number (wild-type (WT) DMM: 532 (SD 56); WT sham: 495 (SD 45); knockout (KO) DMM: 169 (SD 49); KO sham: 187 (SD 56); p < 0.001) and density (WT DMM: 2.2 (SD 0.9); WT sham: 1.2 (SD 0.5); KO DMM: 13.0 (SD 0.5); KO sham: 14.4 (SD 0.7)) of growth plate bridges in Socs2 -/- in comparison with WT. Histological examination of WT and Socs2 -/- knees revealed articular cartilage damage with DMM in comparison to sham. Articular cartilage lesion severity scores (mean and maximum) were similar in WT and Socs2 -/- mice with either DMM, or with ageing. Micro-CT analysis revealed significant decreases in SCB thickness, epiphyseal trabecular number, and thickness in the medial compartment of Socs2 -/-, in comparison with WT (p < 0.001). DMM had no effect on the SCB thickness in comparison with sham in either genotype. Conclusion Together, these data suggest that enhanced GH signalling through SOCS2 deletion accelerates growth plate fusion, however this has no effect on OA vulnerability in this model. Cite this article: Bone Joint Res 2022;11(3):162–170.