Osteoporosis, Osteoarthritis, and Subchondral Insufficiency Fracture: Recent Insights.

The increased incidence of osteoarthritis (OA), particularly knee and hip OA, and osteoporosis (OP), owing to population aging, have escalated the medical expense burden. Osteoarthritis is more prevalent in older women, and the involvement of subchondral bone fragility spotlights its association with OP. Notably, subchondral insufficiency fracture (SIF) may represent a more pronounced condition of OA pathophysiology. This review summarizes the relationship between OA and OP, incorporating recent insights into SIF. Progressive SIF leads to joint collapse and secondary OA and is associated with OP. Furthermore, the thinning and fragility of subchondral bone in early-stage OA suggest that SIF may be a subtype of OA (osteoporosis-related OA, OPOA) characterized by significant subchondral bone damage. The high bone mineral density observed in OA may be overestimated due to osteophytes and sclerosis and can potentially contribute to OPOA. The incidence of OPOA is expected to increase along with population aging. Therefore, prioritizing OP screening, early interventions for patients with early-stage OA, and fracture prevention measures such as rehabilitation, fracture liaison services, nutritional management, and medication guidance are essential.

Effect of longer femoral head on leg length, offset, and range of motion in total hip arthroplasty: a simulation study.

In this study, we investigated the relationship between head length, leg length, offset, and dislocation resistance using range of motion (ROM) simulations based on computed tomography data to examine if a longer femoral head reduces the risk of dislocation. The femoral components were set to eliminate leg length differences with a + 0 mm head, and variations for + 4-, + 7-, and + 8-mm heads were analyzed. Offset and ROM were assessed when longer heads were used, with the leg length adjusted to be similar to that of the contralateral side. While internal rotation at flexion and external rotation at extension increased with + 4-mm longer heads, the + 7- and + 8-mm heads did not increase dislocation resistance. When adjusting for leg length, the longer heads showed no significant differences in offset and ROM. Enhancing dislocation resistance by solely increasing the offset with a longer head, while simultaneously adjusting the depth of stem insertion, may be a beneficial intraoperative technique. Although a + 4-mm longer head possibly increases ROM without impingement, heads extended by + 7 or + 8 mm may not exhibit the same advantage. Therefore, surgeons should consider this technique based on the implant design.

Total hip arthroplasty with femoral shortening osteotomy using polished cemented stem vs. modular cementless stem in patients with Crowe type IV developmental dysplasia of the hip.

INTRODUCTION: There is still little information regarding the advantages of a using a polished tapered stem for Crowe Type IV developmental dysplasia of the hip (DDH). This study aimed to investigate the mid-term clinical and radiological outcomes of primary total hip arthroplasty (THA) with femoral shortening osteotomy using modular and polished tapered stems and to compare the results between the modular and polished tapered stems. MATERIALS AND METHODS: This retrospective review included 32 patients (37 hips) with Crowe type IV DDH who underwent primary THA with femoral shortening osteotomy using a modular stem (cementless group, 14 hips) or a polished tapered stem (cement group, 23 hips) between 1996 and 2018. Clinical data and radiographic assessments were reviewed to analyze the differences between the two groups. RESULTS: The mean duration of patient follow-up of the cementless group (134.4 months) was longer than that of the cement group (75.5 months). There were no differences in clinical results, time of bone union, and survival rate between the two groups. However, the cementless group exhibited a higher ratio of intraoperative fracture and thinning of cortical bone including stress shielding, medullary changes, stem alignment changes, and osteolysis, compared to the cement group. CONCLUSIONS: The findings of this study suggest that THA with femoral shortening osteotomy using both cemented and modular stems can provide satisfactory results. However, considering the occurrence of intraoperative fracture and radiographic analysis in the current study, the cement stem may have an advantage for patients with bone fragility and deterioration in bone quality.

Establishment of the removal method of undifferentiated induced pluripotent stem cells coexisting with chondrocytes using R-17F antibody.

Aim: Tumorigenicity of residual undifferentiated induced pluripotent stem cells (iPSCs) is a major concern. The purpose of this study was to investigate the optimal conditions for removal of iPSCs using R-17F antibody, which recognizes specific glycosphingolipids glycans on undifferentiated iPSCs and exhibits selective cytotoxicity to iPSCs. Materials & methods: After adding of R-17F and secondary antibody to co-cultured iPSCs and chondrocytes, residual iPSCs were quantitatively evaluated by iPS specific glycome analysis. Results: Undifferentiated iPSCs were sufficiently removed using R-17F in combination with an equal amount of a secondary antibody. Furthermore, teratomas were not observed upon transplantation of co-cultured cells pretreated under the same conditions into testes of immunodeficient mice. Conclusion: This removal method incorporating R-17F may be useful for regenerative medicine using iPSCs.

Optical coherence tomography evaluation of the spatiotemporal effects of 3D bone marrow stromal cell culture using a bioreactor.

Performing cell culture in a three-dimensional (3D) environment has various advantages. In cartilage tissue engineering, 3D in vitro cultures utilizing biomaterials and bioreactors can mimic the biological environment. However, the biggest drawback of these 3D culture systems is a limited ability to evaluate 3D cell distribution. Optical coherence tomography (OCT) has recently been used to evaluate 3D cellular morphology and structure in a timely manner. Here, we showed that OCT could be used to visually assess the distribution and the morphology of bone marrow stromal cells under chondrogenic 3D cultivation using alginate gels and rotary culture. In particular, OCT was able to visualize living cells embedded in alginate gels in a non-destructive and 3D manner, as well as quantitatively evaluate cell distribution and spheroid volume. We also found that cells were centralized in rotary culture but peripherally distributed in static culture, while rotary culture enhanced the hypertrophy of marrow stromal cells (MSCs) embedded in alginate gels. Together, our findings demonstrate that OCT can be used to evaluate the spatiotemporal effects of 3D cultivation using alginate gels and rotary culture. Therefore, this method may allow the observation of pre-cultured tissue over time and the optimization of culture conditions for regenerative tissue engineering.

Effect of periacetabular osteotomy on the distribution pattern of subchondral bone mineral density in patients with hip dysplasia.

Despite the availability of long-term follow-up data, the effect of pelvic osteotomy on the natural history of osteoarthritis is not yet fully understood, partly because there is untapped potential for radiographs to better describe osteoarthritis. Therefore, this study aimed to assess the distribution of subchondral bone mineral density (BMD) across the acetabulum in patients with hip dysplasia immediately (2 weeks) and 1 year after undergoing periacetabular osteotomy (PAO). To that end, we reviewed 40 hips from 33 patients with developmental dysplasia of the hip who underwent PAO between January 2016 and July 2019 at our institution. We measured subchondral BMD through the articular surface of the acetabulum using computed tomography osteoabsorptiometry, dividing the distribution map into nine segments. We then compared the subchondral BMD between 2 weeks and 1 year after PAO in each area. At 2 weeks after PAO, the high-density area tended to be localized particularly in the lateral part of the acetabulum, whereas 1 year after PAO, the high-density area moved to the central and lateral parts. The percentage ratios of the subchondral BMD for the central-posterior, lateral-central, and lateral-posterior areas relative to the central-central area were significantly decreased at 1 year after PAO, as compared to those at 2 weeks after PAO. These findings suggest that loading was altered by PAO to be more similar to physiological loading. A long follow-up observational study is warranted to confirm the association between early changes in subchondral BMD by PAO and joint degeneration.

Local Administration of Low-Dose Nerve Growth Factor Antibody Reduced Pain in a Rat Osteoarthritis Model.

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague-Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.

Alterations of Glycosphingolipid Glycans and Chondrogenic Markers during Differentiation of Human Induced Pluripotent Stem Cells into Chondrocytes.

Due to the limited intrinsic healing potential of cartilage, injury to this tissue may lead to osteoarthritis. Human induced pluripotent stem cells (iPSCs), which can be differentiated into chondrocytes, are a promising source of cells for cartilage regenerative therapy. Currently, however, the methods for evaluating chondrogenic differentiation of iPSCs are very limited; the main techniques are based on the detection of chondrogenic genes and histological analysis of the extracellular matrix. The cell surface is coated with glycocalyx, a layer of glycoconjugates including glycosphingolipids (GSLs) and glycoproteins. The glycans in glycoconjugates play important roles in biological events, and their expression and structure vary widely depending on cell types and conditions. In this study, we performed a quantitative GSL-glycan analysis of human iPSCs, iPSC-derived mesenchymal stem cell like cells (iPS-MSC like cells), iPS-MSC-derived chondrocytes (iPS-MSC-CDs), bone marrow-derived mesenchymal stem cells (BMSCs), and BMSC-derived chondrocytes (BMSC-CDs) using glycoblotting technology. We found that GSL-glycan profiles differed among cell types, and that the GSL-glycome underwent a characteristic alteration during the process of chondrogenic differentiation. Furthermore, we analyzed the GSL-glycome of normal human cartilage and found that it was quite similar to that of iPS-MSC-CDs. This is the first study to evaluate GSL-glycan structures on human iPS-derived cartilaginous particles under micromass culture conditions and those of normal human cartilage. Our results indicate that GSL-glycome analysis is useful for evaluating target cell differentiation and can thus support safe regenerative medicine.

Evaluation of Residual Human-Induced Pluripotent Stem Cells in Human Chondrocytes by Cell Type-Specific Glycosphingolipid Glycome Analysis Based on the Aminolysis-SALSA Technique.

Cartilage damage may eventually lead to osteoarthritis because it is difficult to repair. Human-induced pluripotent stem cell (iPSC)-derived chondrocytes may potentially be used to treat cartilage damage, but the tumorigenicity of iPSCs is a major concern for their application in regenerative medicine. Many glycoconjugates serve as stem cell markers, and glycosphingolipids (GSLs) including H type 1 antigen (Fucα1-2Galß1-3GlcNAc) have been expressed on the surface of iPSCs. The purpose of the present study was to investigate whether GSL-glycome analysis is useful for quality control of residual iPSCs in chondrocytes. We performed GSL-glycome analysis of undifferentiated iPSCs in chondrocytes by combining glycoblotting and aminolysis-sialic acid linkage-specific alkylamidation (SALSA) method, enabling the detection of small quantities of iPSC-specific GSL-glycans from 5 × 104 cells. Furthermore, we estimated the residual amount of iPSCs using R-17F antibody, which possesses cytotoxic activity toward iPSCs that is dependent on the Lacto-N-fucopentaose I (LNFP I) of GSL. Moreover, we could detect a small number of LNFP I during mesenchymal stem cells (MSCs) differentiation from iPSCs. This is the first demonstration that GSL-glycome analysis is useful for detecting undifferentiated iPSCs, and can thereby support safe regenerative medicine.

[A case of sigmoid colon cancer with lymphangitis carcinomatosa successfully treated with chemotherapies including molecular targeting drugs].

A 51-year-old man was referred to our hospital with adenocarcinoma of sigmoid colon with multiple lymph node metastasis. At the time of admission, he had dyspnea, and computed tomography (CT) showed typical signs of lymphangitis carcinomatosa of the lung. Combination of mFOLFOX6 and bevacizumab was started. After start of the therapy, CT revealed an improvement in lymphangitis carcinomatosa. 8 months later, the tumor assessment became progressive disease. FOLFIRI was started as the second-line chemotherapy, but the patient did not respond. Then, dyspnea emerged again, and CT indicated the lymphangitis carcinomatosa had become worse. So as the third-line chemotherapy, combination of irinotecan and cetuximab was started. Dyspnea immediately disappeared, and CT showed an improvement of lymphangitis carcinomatosa. In the previous literature, malignant tumor cases which accompany lymphangitis carcinomatosa might always have a poor course. Our case dramatically responded to the chemotherapy including molecular targeting drug and showed a long survival. So we conclude that aggressive chemotherapy including a molecular targeting drug may be recommended in a case of colorectal cancer which accompanies lymphangitis carcinomatosa of the lung.