Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model.

The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.

Osteochondroma Pathogenesis: Mouse Models and Mechanistic Insights into Interactions with Retinoid Signaling.

Osteochondromas are cartilage-capped tumors that arise near growing physes and are the most common benign bone tumor in children. Osteochondromas can lead to skeletal deformity, pain, loss of motion, and neurovascular compression. Currently, surgery is the only available treatment for symptomatic osteochondromas. Osteochondroma mouse models have been developed to understand the pathology and the origin of osteochondromas and develop therapeutic drugs. Several cartilage regulatory pathways have been implicated in the development of osteochondromas, such as bone morphogenetic protein, hedgehog, and WNT/ß-catenin signaling. Retinoic acid receptor-γ is an important regulator of endochondral bone formation. Selective agonists for retinoic acid receptor-γ, such as palovarotene, have been investigated as drugs for inhibition of ectopic endochondral ossification, including osteochondromas. This review discusses the signaling pathways involved in osteochondroma pathogenesis and their possible interactions with the retinoid pathway.

Treatment Approach for Knee Osteoarthritis with Ipsilateral Femoral Cartilage Tumor: A Case Series.

Osteoarthritis (OA) is a common pathology affecting the knee joint. Twenty percent of the cartilaginous tumors of bone are in the distal femur. This presents a challenge for treating patients with knee OA who also have ipsilateral distal femur cartilage tumors. We propose a classification system for knee OA with ipsilateral cartilaginous tumor and a treatment approach to address this issue. Intramedullary guides are avoided when performing total knee arthroplasty (TKA) in these patients so as not to further contaminate the femur with tumor cells. A non-image-based stereotactic surgical system is favored at our institution to achieve this goal. Seven patients underwent classification and treatment with TKA utilizing this approach. Average final follow-up was 15.3 months. Component alignment averaged 89.2° and all patients had 0° of extension with an average flexion to 107.5°. There were no postoperative complications and no radiographic evidence of component complication, tumor recurrence, or tumor expansion. Few studies have reported on the treatment of knee OA with concurrent cartilaginous tumor of the distal femur. All patients treated with the proposed approach had their OA successfully treated without complication related to their cartilaginous tumor or TKA components. This case series presents a novel classification and treatment algorithm to potentially guide arthroplasty surgeons in approaching these often-concurrent occurring pathologies.

Incidental long bone cartilage lesions: is any further imaging workup needed?

OBJECTIVE: To determine the rate of chondrosarcoma in incidentally discovered painless long bone cartilage lesions and to determine if any further imaging is needed. MATERIALS AND METHODS: A cartilage lesion was said to be an enchondroma when it had characteristic matrix mineralization and no aggressive features. Search of all imaging reports and tumor board files for keywords enchondroma, cartilage lesion, chondroid, and chondrosarcoma. Retrospective review of medical records and imaging studies from 4.5-year period. Data points collected included patient age, sex, lesion site, size, symptoms, type of imaging, imaging appearance, and length of follow-up. Only patients with no pain were included as enchondroma. Patients with final diagnosis of chondrosarcoma were included for comparison of all features. RESULTS: Only 1/73 (1.4%) patients with an initial incidentally discovered painless lesion was later diagnosed, with new symptoms, as atypical cartilage tumor. Average age was 59.4 years. Bones involved were the femur (n = 33), humerus (n = 30), tibia (n = 7), fibula (n = 2), and ulna (n = 1). Average enchondroma size was 3.9 cm (range 1.4-11.5). Average follow-up was 47 months (range 2-196 months). Eleven long bone chondrosarcomas were identified. All chondrosarcoma patients had pain and aggressive imaging findings. CONCLUSION: Our study reveals that the rate of chondrosarcoma in incidentally found painless chondroid lesions without aggressive features in long bones is low. Imaging follow-up may be needed only in the setting of new symptoms.

Bizarre parosteal osteochondromatous proliferation: 16 Cases with a focus on histologic variability.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a benign bone and cartilage forming tumor occurring on the surface of bones, predominantly on the hands and feet. A defining feature of BPOP is the purplish-blue mineralization of cartilaginous tissue, known as 'blue bone.' Here, we report on an institutional series of 16 cases of BPOP, including radiographic, histologic, and histomorphometric features. All tumors were composed of some element of bone, cartilage, fibrous tissue and 'blue bone,' though the amount of each tissue sub-type varied widely. Some cases showed focal 'blue bone' only, however this was a defining feature in all cases.

Ptpn11 Deletion in CD4+ Cells Does Not Affect T Cell Development and Functions but Causes Cartilage Tumors in a T Cell-Independent Manner.

The ubiquitously expressed tyrosine phosphatase Src homology region 2 domain-containing phosphatase-2 (SHP-2, encoded by Ptpn11) is required for constitutive cellular processes including proliferation, differentiation, and the regulation of immune responses. During development and maturation, subsets of T cells express a variety of inhibitory receptors known to associate with phosphatases, which in turn, dephosphorylate key players of activating receptor signaling pathways. We hypothesized that SHP-2 deletion would have major effects on T cell development by altering the thresholds for activation, as well as positive and negative selection. Surprisingly, using mice conditionally deficient for SHP-2 in the T cell lineage, we show that the development of these lymphocytes is globally intact. In addition, our data demonstrate that SHP-2 absence does not compromise T cell effector functions, suggesting that SHP-2 is dispensable in these cells. Unexpectedly, in aging mice, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in wrist bones in a T cell-independent manner. These tumors resemble miniature cartilaginous growth plates and contain CD4-lineage positive chondrocyte-like cells. Altogether these results indicate that SHP-2 is a cartilage tumor suppressor during aging.

Mutant IDH is sufficient to initiate enchondromatosis in mice.

Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

Mesenchymal chondrosarcoma of posterior maxilla: report of a case with brief literature review.

Mesenchymal chondrosarcomas (MCs) are infrequent, slow-growing malignant tumors of head and neck region affecting both bone and soft tissues. It represents approximately 1% of all chondrosarcomas. They usually occur in the middle aged individuals, but rarely seen in young patients. It is commonly found in the ribs and jaws. Involvement of the jaws is evident in 22-27% of cases of MC. Most commonly, MCs are painless and occurs in the anterior portion of maxilla. Maxillofacial MCs are aggressive, has a tendency for recurrence and late metastasis to lung, bone, and lymph nodes, and is associated with an overall poor prognosis. Histopathologically, it is characterized by a biphasic pattern consisting of areas of hyaline cartilage mixed with small cell malignancy. Very few case reports involving the posterior maxillary region has been reported. This article reports a rare case of MC along with a review of the pertinent literature.