Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo.

Direct therapeutic gene transfer is a promising tool to treat articular cartilage defects. Here, we tested the ability of an recombinant adeno-associated virus (rAAV) insulin-like growth factor I (IGF-I) vector to improve the early repair of cartilage lesions in vivo. The vector was administered for 3 weeks in osteochondral defects created in the knee joints of rabbits compared with control (lacZ) treatment and in cells that participate in the repair processes (mesenchymal stem cells, chondrocytes). Efficient IGF-I expression was observed in the treated lesions and in isolated cells in vitro. rAAV-mediated IGF-I overexpression was capable of stimulating the biologic activities (proliferation, matrix synthesis) both in vitro and in vivo. IGF-I treatment in vivo was well tolerated, revealing significant improvements of the repair capabilities of the entire osteochondral unit. IGF-I overexpression delayed terminal differentiation and hypertrophy in the newly formed cartilage, possibly due to contrasting effects upon the osteogenic expression of RUNX2 and ß-catenin and to stimulating effects of this factor on the parathyroid hormone/parathyroid hormone-related protein pathway in this area. Production of IGF-I improved the reconstitution of the subchondral bone layer in the defects, showing increased RUNX2 expression levels in this zone. These findings show the potential of directly applying therapeutic rAAVs to treat cartilage lesions.

Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up.

PURPOSE: To analyze the results of the use of intra-articular cultured autologous bone marrow-derived mesenchymal stem cell (MSC) injections in conjunction with microfracture and medial opening-wedge high tibial osteotomy (HTO). METHODS: Fifty-six knees in 56 patients with unicompartmental osteoarthritic knees and genu varum were randomly allocated to the cell-recipient group (n = 28) or control group (n = 28). Patients who had a joint line congruity angle of more than 2°, malalignment of the knee from femoral causes, a fixed flexion deformity, or age older than 55 years were excluded. All patients underwent HTO and microfracture. The cell-recipient group received intra-articular injection of cultured MSCs with hyaluronic acid 3 weeks after surgery, whereas the control group only received hyaluronic acid. The primary outcome measure was the International Knee Documentation Committee (IKDC) score at intervals of 6 months, 1 year, and 2 years postoperatively. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. RESULTS: The median age of the patients was 51 years, with a mean body mass index of 23.85. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the cell-recipient group showed significantly better scores. The effect of treatment showed an added improvement of 7.65 (95% confidence interval [CI], 3.04 to 12.26; P = .001) for IKDC scores, 7.61 (95% CI, 1.44 to 13.79; P = .016) for Lysholm scores, and 0.64 (95% CI, 0.10 to 1.19; P = .021) for Tegner scores. Magnetic resonance imaging scans performed 1 year after surgical intervention showed significantly better MOCART scores for the cell-recipient group. The age-adjusted mean difference in MOCART score was 19.6 (95% CI, 10.5 to 28.6; P < .001). CONCLUSIONS: Intra-articular injection of cultured MSCs is effective in improving both short-term clinical and MOCART outcomes in patients undergoing HTO and microfracture for varus knees with cartilage defects. LEVEL OF EVIDENCE: Level II, randomized controlled trial.

Hip ontogenesis: how evolution, genes, and load history shape hip morphotype and cartilotype.

BACKGROUND: Developmental hip disorders (DHDs), eg, developmental dysplasia of the hip, slipped capitis femoris epiphysis, and femoroacetabular impingement, can be considered morphology variants of the normal hip. The femoroacetabular morphology of DHD is believed to induce osteoarthritis (OA) through local cumulative mechanical overload acting on genetically controlled patterning systems and subsequent damage of joint structures. However, it is unclear why hip morphology differs between individuals with seemingly comparable load histories and why certain hips with DHD progress to symptomatic OA whereas others do not. QUESTIONS/PURPOSES: We asked (1) which mechanical factors influence growth and development of the proximal femur; and (2) which genes or genetic mechanisms are associated with hip ontogenesis. METHODS: We performed a systematic literature review of mechanical and genetic factors of hip ontogeny. We focused on three fields that in recent years have advanced our knowledge of adult hip morphology: imaging, evolution, and genetics. WHERE ARE WE NOW?: Mechanical factors can be understood in view of human evolutionary peculiarities and may summate to load histories conducive to DHD. Genetic factors most likely act through multiple genes, each with modest effect sizes. Single genes that explain a DHD are therefore unlikely to be found. Apparently, the interplay between genes and load history not only determines hip morphotype, but also joint cartilage robustness ("cartilotype") and resistance to symptomatic OA. WHERE DO WE NEED TO GO?: We need therapies that can improve both morphotype and cartilotype. HOW DO WE GET THERE?: Better phenotyping, improving classification systems of hip morphology, and comparative population studies can be done with existing methods. Quantifying load histories likely requires new tools, but proof of principle of modifying morphotype in treatment of DDH and of cartilotype with exercise is available.

The trochlear cleft: the "black line" of the trochlear trough.

OBJECTIVE: The "cartilage black line sign" is a recently described T2 dark cartilage lesion that we have identified appearing as a cleft in the trochlear trough. The purpose of our study was to define the MR imaging characteristics of a trochlear cleft, determine its incidence, and correlate the MR findings with arthroscopy. MATERIALS AND METHODS: A total of 1,300 consecutive MR examinations of the knee were retrospectively reviewed by consensus of two fellowship-trained musculoskeletal radiologists. The MR imaging characteristics and location of a trochlear cleft were determined. Imaging results were compared to arthroscopy when available. Patient age and gender were compared to 25 randomly selected control patients without trochlear clefts. RESULTS: A total of 25 (1.9%) individuals (11 females and 14 males; age range 19­45 years; mean age 28 years) were diagnosed with a trochlear cleft. The control group consisted of 11 females and 14 males; age range 19­83 years; mean age 46 years. Mean cleft length was 7 mm (range 6­12 mm); cleft location was consistently in the lower trochlear trough. No full-thickness cartilage defects were identified in the eight individuals in whom arthroscopic correlation was available. A grade 2 cartilage lesion was identified in a single individual; another progressed from grade 0 to a full-thickness trochlear lesion over an 8-month interval. Eight individuals were athletes. No significant difference in gender was noted between the two groups, however, the study group was significantly younger p<0.0001. CONCLUSIONS: A trochlear cleft is a rare finding in young active individuals. It most likely indicates an incomplete cartilage fissure which may rarely progress to a full-thickness defect.

Ligament and bone pathologic abnormalities more frequent in neuropathic joint disease in comparison with degenerative arthritis of the foot and ankle: implications for understanding rapidly progressive joint degeneration.

OBJECTIVE: The variable disease progression of osteoarthritis (OA) and the basis for rapid joint deterioration in some subgroups of patients are poorly understood. To explore an anatomic basis for rapidly progressive OA, this observational study compared the magnetic resonance imaging (MRI) patterns of disease between patients with neuropathic joint disease (NJD) and patients with degenerative arthritis of the ankle and foot. METHODS: MR images of the foot and ankle of patients with early NJD (n = 7) and patients with OA (n = 15) were assessed. The anonomized MR images were dichotomously scored by a musculoskeletal radiologist for the presence of the following abnormalities per bone (of a total of 14 bones): cartilage defects, bone cysts, bone marrow edema, fractures, joint debris, joint effusions, tendinopathy, tendinitis, and ligament tears. RESULTS: Although the degree of cartilage damage and joint cyst formation was comparable between the groups, the degree of ligament tears, or change in MRI signal intensity in the ligaments, was significantly greater in patients with NJD compared with patients with OA (median of 3 tears versus 0, of 14 total bones; P < 0.01). Moreover, in patients with early NJD compared with patients with OA, there was a significantly greater degree of diffuse bone marrow edema (median of 6.5 tarsal bones versus 2 adjacent bones, of 14 total bones; P < 0.01), a greater number of bone fractures (median 4 versus 0; P < 0.01), and more frequent bone debris (median 4.5 versus 0; P = 0.013). CONCLUSION: This analysis of NJD in the foot and ankle shows the predominance of bone and ligament abnormalities in NJD compared with the pattern of involvement in OA. These findings highlight the importance of structures other than articular cartilage in OA of the ankle and foot, and suggest that rapid joint degeneration in NJD may be more ligamentogenic or osteogenic in nature.

The Fragility of Statistical Significance in Cartilage Restoration of the Knee: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: The purpose of this study was to utilize fragility analysis to assess the robustness of randomized controlled trials (RCTs) evaluating the management of articular cartilage defects of the knee. We hypothesize that the cartilage restorative literature will be fragile with the reversal of only a few outcome events required to change statistical significance. DESIGN: RCTs from 11 orthopedic journals indexed on PubMed from 2000 to 2020 reporting dichotomous outcome measures relating to the management of articular cartilage defects of the knee were included. The Fragility Index (FI) for each outcome was calculated through the iterative reversal of a single outcome event until significance was reversed. The Fragility Quotient (FQ) was calculated by dividing each FI by study sample size. Additional statistical analysis was performed to provide median FI and FQ across subgroups. RESULTS: Nineteen RCTs containing 60 dichotomous outcomes were included for analysis. The FI and FQ of all outcomes was 4 (IQR 2-7) and 0.067 (IQR 0.034-0.096), respectively. The average number of patients lost to follow-up (LTF) was 3.9 patients with 15.8% of the included studies reporting LTF greater than or equal to 4, the FI of all included outcomes. CONCLUSIONS: The orthopedic literature evaluating articular cartilage defects of the knee is fragile as the reversal of relatively few outcome events may alter the significance of statistical findings. We therefore recommend comprehensive fragility analysis and triple reporting of the P value, FI, and FQ to aid in the interpretation and contextualization of clinical findings reported in the cartilage restoration literature.

Transient activation of Wnt/{beta}-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice.

Wnt/beta-catenin signaling is required for skeletal development and organization and for function of the growth plate and articular cartilage. To further clarify these roles and their possible pathophysiological importance, we created a new transgenic mouse model in which Wnt/beta-catenin signaling can be activated in cartilage for specific periods of time. These transgenic mice expressed a constitutive active form of beta-catenin fused to a modified estrogen receptor ligand-binding domain under the control of cartilage-specific collagen 11alpha2 promoter/enhancer. Transient Wnt/beta-catenin signaling activation in young adult mice by tamoxifen injections induced growth retardation and severe deformities in knee joints. Tibial and femoral growth plates displayed an excessive number of apoptotic cells and eventually underwent abnormal regression. Articular cartilage exhibited an initial acute loss of proteoglycan matrix that was followed by increases in thickness, cell density, and cell proliferation. In reciprocal studies, we found that conditional ablation of beta-catenin in postnatal mice using a Col2-CreER strategy led to hypocellularity in articular cartilage, growth plate disorganization, and a severe reduction in bone volume. Together, these data provide evidence that Wnt/beta-catenin signaling has important and distinct roles in growth plate and articular cartilage and that postnatal dysregulation of this signaling pathway causes diverse structural and functional changes in the two cartilaginous structures.

Magnetic resonance imaging of articular cartilage abnormalities of the far posterior femoral condyle of the knee.

BACKGROUND: Incidental articular cartilage lesions of the far posterior femoral condyle (FPFC) are commonly detected. Whether or not these cartilage lesions are symptomatic or clinically significant is unknown. PURPOSE: To characterize and assess prevalence of articular cartilage abnormalities of the FPFC and associated bone marrow edema (BME) and/or internal derangements through magnetic resonance (MR) images. MATERIAL AND METHODS: 654 knee MR examinations were reviewed retrospectively. Sagittal fast spin-echo proton density-weighted images with and without fat suppression were acquired with a 1.5T scanner, and were evaluated by two readers by consensus. The following factors were assessed: 1) the prevalence of cartilage abnormalities, 2) laterality, 3) the type of cartilage abnormalities, 4) cartilage abnormality grading, 5) associated BME, 6) complications such as meniscal injury and cruciate ligament injury, and 7) knee alignment (femorotibial angle [FTA]). RESULTS: Articular cartilage abnormalities of the FPFC were demonstrated in 157 of the 654 patients (24%). Of these, 40 patients demonstrated medial and lateral FPFC cartilage abnormalities and were thus counted as 80 cases. Focal lateral FPFC abnormalities were demonstrated in 117 of 197 cases (59.4%), while diffuse lateral FPFC abnormalities were demonstrated in 24 of 197 cases (12.2%). Focal medial FPFC abnormalities were demonstrated in 23 of 197 cases (11.6%), while diffuse medial FPFC abnormalities were demonstrated in 33 of 197 cases (16.8%). No statistically significant pattern of associated BME, FTA, or internal derangements including meniscal and cruciate ligament injury was demonstrated. CONCLUSION: Articular cartilage abnormalities of the FPFC are common and were demonstrated in 24% of patients or 30% of cases. Lateral FPFC abnormalities occur 2.5 times more frequently than medial FPFC abnormalities and were more frequently focal compared with medial cohorts. BME is associated in 36.5% of cases.

Relationship between degree of malocclusion and occlusal interference in mice that spontaneously develop anterior transverse crossbite.

INTRODUCTION: Mice with brachymorphism (bm) have defective chondrogenesis, including abnormal growth of the spheno-occipital synchondrosis. Malocclusion (anterior transverse crossbite) sometimes spontaneously occurs in inbred BALB/c-bm/bm mice, before the mandibular incisors erupt and make contact with the maxillary incisors. The aim of this study was to determine whether functional lateral loads to incisors promote anterior transverse crossbites in BALB/c-bm/bm mice. METHODS: BALB/c-bm/bm mice with normal occlusion (normal group), BALB/c-bm/bm mice with malocclusion in which the incisors were not cut (mal group), and BALB/c-bm/bm mice in which the incisors had been cut to eliminate the functional lateral load during continued growth (mal-cut group) were used. We examined the amounts of shift of the maxillary and mandibular incisors in each group using radiographic images. RESULTS: The amount of shift of the maxillary incisors in the mal group was significantly greater than that in normal group. The total amount of shift from the maxilla to the mandible in the mal group was significantly greater than in the normal and mal-cut groups. CONCLUSIONS: The results suggest that a continuous functional lateral load to the incisors is strongly related to promoting and worsening anterior transverse crossbite in BALB/c-bm/bm mice.

Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin-1, thrombospondin-3, thrombospondin-5, and type IX collagen.

Thrombospondin-5 (TSP5) is a large extracellular matrix glycoprotein found in musculoskeletal tissues. TSP5 mutations cause two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia; both show a characteristic growth plate phenotype with retention of TSP5, type IX collagen (Col9), and matrillin-3 in the rough endoplasmic reticulum. Whereas most studies focus on defining the disease process, few functional studies have been performed. TSP5 knockout mice have no obvious skeletal abnormalities, suggesting that TSP5 is not essential in the growth plate and/or that other TSPs may compensate. In contrast, Col9 knockout mice have diminished matrillin-3 levels in the extracellular matrix and early-onset osteoarthritis. To define the roles of TSP1, TSP3, TSP5, and Col9 in the growth plate, all knockout and combinatorial strains were analyzed using histomorphometric techniques. While significant alterations in growth plate organization were found in certain single knockout mouse strains, skeletal growth was only mildly disturbed. In contrast, dramatic changes in growth plate organization in TSP3/5/Col9 knockout mice resulted in a 20% reduction in limb length, corresponding to similar short stature in humans. These studies show that type IX collagen may regulate growth plate width; TSP3, TSP5, and Col9 appear to contribute to growth plate organization; and TSP1 may help define the timing of growth plate closure when other extracellular proteins are absent.

Association of glenoid morphology and anterosuperior labral variation.

OBJECTIVE: The objective of this study was to determine whether glenoid morphology correlates with anterosuperior labral variation. METHODS: Eighty-eight direct shoulder magnetic resonance arthrograms were retrospectively reviewed. Sagittal oblique images were assessed for the presence or absence of anterosuperior glenoid concavity. Evaluation of axial images was performed, separately classifying the anterosuperior labrum into 1 of 4 categories: no variation, diminutive labrum, sublabral foramen, or Buford complex. RESULTS: In 88 shoulders, there were 13 notched glenoids (15%). In this group, 3 (23%) had a Buford complex, 2 (15%) had a sublabral foramen, and 4 (31%) had a diminutive labrum. There were 75 ovoid glenoids (85%). In this group, 3 (4%) had a Buford complex, 8 (11%) had a sublabral foramen, and 7 (9%) had a diminutive labrum. There was a significant association (P = 0.001) between notched glenoid morphology and developmental variation of the anterosuperior labrum. CONCLUSIONS: The presence of anterior glenoid concavity is significantly associated with overlying labral variation, which may be of use in discriminating labral pathology from developmental variation.

Labral disease associated with femoroacetabular impingement: do we need to correct the structural deformity?

In this study, we compared the clinical results of arthroscopic partial labral resection to augmentation of this procedure with limited open osteochondroplasty for the treatment of symptomatic femoroacetabular impingement. Two consecutive cohorts were evaluated: (a) group I, arthroscopic treatment of labrum and articular cartilage, and (b) group II, hip arthroscopy augmented with limited osteochondroplasty of the femoral head-neck junction. Group I (23 hips) and group II (25 hips) patients had no difference in age, labral disease patterns, osteoarthritis grade, or chondromalacia. Mean follow-up was slightly longer in group I. The modified Harris Hip Score showed a trend toward higher values in group II. A 10-point improvement was more common in group II, and fewer group II patients required subsequent surgery. These preliminary data suggest that patients with cam femoroacetabular impingement may have improved clinical outcomes when the impingement deformity is corrected.

Abnormal mandibular growth and the condylar cartilage.

Deviations in the growth of the mandibular condyle can affect both the functional occlusion and the aesthetic appearance of the face. The reasons for these growth deviations are numerous and often entail complex sequences of malfunction at the cellular level. The aim of this review is to summarize recent progress in the understanding of pathological alterations occurring during childhood and adolescence that affect the temporomandibular joint (TMJ) and, hence, result in disorders of mandibular growth. Pathological conditions taken into account are subdivided into (1) congenital malformations with associated growth disorders, (2) primary growth disorders, and (3) acquired diseases or trauma with associated growth disorders. Among the congenital malformations, hemifacial microsomia (HFM) appears to be the principal syndrome entailing severe growth disturbances, whereas growth abnormalities occurring in conjunction with other craniofacial dysplasias seem far less prominent than could be anticipated based on their often disfiguring nature. Hemimandibular hyperplasia and elongation undoubtedly constitute the most obscure conditions that are associated with prominent, often unilateral, abnormalities of condylar, and mandibular growth. Finally, disturbances of mandibular growth as a result of juvenile idiopathic arthritis (JIA) and condylar fractures seem to be direct consequences of inflammatory and/or mechanical damage to the condylar cartilage.

Long-Term Clinical and MRI Results of Matrix-Assisted Autologous Chondrocyte Implantation for Articular Cartilage Defects of the Knee.

OBJECTIVE: To evaluate the long-term clinical and radiological outcome of matrix-assisted autologous chondrocyte implantation (mACI) for articular cartilage defects in the knee joint. DESIGN: Clinical evaluation was assessed in 21 patients with full-thickness cartilage defects, International Cartilage Repair Society (ICRS) grade IV. Clinical scoring was performed preoperatively and 12 years after transplantation using the International Knee Documentation Committee (IKDC) score, the Lysholm score, the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Noyes sports activity rating scale. Morphologic evaluation of the repair tissue was assessed by magnetic resonance imaging (MRI) in 14 patients using the Kreuz-Henderson score. RESULTS: Clinical evaluation revealed significant improvement in the IKDC, the Lysholm, the KOOS, and the Noyes score. Morphological evaluation by MRI showed moderate to complete defect filling in 10 of 14 patients, demonstrating normal to nearly normal values in mean 74.29% of all assessed parameters. Significant correlation of the parameter cartilage signal and clinical outcome was found with the IKDC, Lysholm, and KOOS subscales ADL (activities of daily living) and QoL (quality of life). CONCLUSIONS: The clinical and radiological outcomes 12 years after transplantation suggest the confirmation of the promising results of the mid-term follow-up. This study therefore provides first indications that the implantation of mACI might be a suitable option for long-term cartilage repair. Future controlled studies need to address the exact parameters influencing the long-term outcome of mACI.

Acetabular Delamination: Epidemiology, Histological Features, and Treatment.

OBJECTIVE: The International Cartilage Repair Society classification is the one mainly used to define chondral defects. However, this classification does not include delamination. The objective of the study is to describe the characteristics of this lesion to better explain its classification in the context of chondral lesions of the hip. DESIGN: We performed a retrospective analysis of 613 patients who underwent hip arthroscopy. In this group, the incidence, localization, histological characteristics, and association to femoroacetabular impingement as well as to other intraarticular lesions of acetabular delamination (AD) were analyzed. Preoperative magnetic resonance imaging accuracy and the different treatment options were also evaluated. RESULTS: In our series, the incidence of the AD was 37% (226 patients over 613). The average age of this group was significantly lower (39.3 years) than the entire group of patients. Isolated cam (P < 0.01) and pincer morphologies (P < 0.05) had a significant statistical association with the AD. This lesion was primarily localized at the acetabular chondrolabral junction, mainly on the anterosuperior quadrant. The intraarticular lesions more frequently associated to AD were labral lesions (94.25%, P < 0.01), ligamentum teres lesions (28.32%, P < 0.05), and femoral head chondral lesions (19.9%, P < 0.01). The histological examination of the AD was characterized by hypocellularity and structural disorder of the matrix, with fissures. Treatment remains controversial. CONCLUSION: AD represents an intermediate stage in chondral damage and can be classified as a "2a" grade lesion. Histological examination confirms the intermediate and progressive character of this injury.

Management of Articular Cartilage Defects in the Glenohumeral Joint.

Articular cartilage defects are not often encountered in the glenohumeral joint. These lesions are typically found in patients with shoulder trauma, recurrent instability, or previous surgical treatment. Diagnosis can be difficult; these defects are often found incidentally during arthroscopic or open surgical management of other pathology. Initial management of isolated glenohumeral chondral defects is nonsurgical and includes physical therapy and/or corticosteroid injections. If nonsurgical treatment is unsuccessful, patients may undergo surgery. Because these lesions occur infrequently, few studies have documented surgical techniques and outcomes. Surgical strategies include arthroscopic débridement, microfracture surgery, osteochondral autograft or allograft transplantation, autologous chondrocyte implantation, and particulated juvenile allograft cartilage implantation.

Bilateral Hypoplasia of Both Medial and Lateral Menisci Partially Fused With the Cartilage Surface of the Tibial Plateau.

Hypoplastic meniscus is an extremely rare abnormality. The authors present the first case of meniscal hypoplasia with a partial fusion of meniscus and tibial cartilage. A 22-year-old man underwent surgery for a chronic patellar dislocation. Preoperative magnetic resonance imaging and arthroscopy incidentally revealed hypoplasia of both medial and lateral menisci. Moreover, the posterior horn of the medial meniscus and middle body of the lateral meniscus were fused with the cartilage surface of the tibia. Magnetic resonance imaging of the contralateral knee showed similar meniscal anomalies. This case presents an interesting and extremely rare abnormality of the meniscus. [Orthopedics. 2018; 41(6):e884-e887.].

Collagen XI mutation lowers susceptibility to load-induced cartilage damage in mice.

Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5 N) and high (9.0 N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:711-720, 2018.

Osteochondral defect repair with autologous bone marrow-derived mesenchymal stem cells in an injectable, in situ, cross-linked synthetic extracellular matrix.

A co-cross-linked synthetic extracellular matrix (sECM) composed of chemically modified hyaluronic acid and gelatin was used as a cell delivery vehicle for osteochondral defect repair in a rabbit model. A full-thickness defect was created in the patellar groove of the femoral articular cartilage in each of 2 rabbit joints, and 4 experimental groups were assigned (12 rabbits/group): untreated control, autologous mesenchymal stem cells (MSCs) only, sECM only, and MSCs + sECM. The sECM hydrogels were allowed to cross-link in the defect in situ. Rabbits were sacrificed at 4, 8, and 12 weeks post-surgery, and cartilage repair was evaluated and scored. In the controls, defects were filled with fibrous tissue. In the MSC-only group, hyaline-like cartilage filled the peripheral area of the defect, but the center was filled with fibrous tissue. In the sECM-only group, hyaline cartilage with zonal architecture filled the defect at 12 weeks, but an interface between repaired and adjacent host cartilage was evident. In the MSCs + sECM group, defects were completely filled with elastic, firm, translucent cartilage at 12 weeks and showed superior integration of the repair tissue with the normal cartilage. The sECM delivers and retains MSCs, and the injectable cell-seeded sECM could be delivered arthroscopically in the clinic.