Return-to-Sport Rate, Type of Sport, Frequency of Participation, and Patient Satisfaction After Elective Spinal Surgery in the Elderly Population.

Background: The number of elderly sports participants is increasing, and the possibility of return to sport (RTS) has become an important part of surgical decision making in this population. Purpose: To investigate RTS after elective spinal surgery in elderly patients. Study Design: Case series; Level of evidence, 4. Methods: We enrolled patients aged ≥65 years with a history of preoperative or preinjury sports participation who underwent elective spinal surgery at a single institution between 2019 and 2021. At minimum 12-month follow-up, a questionnaire was administered to each participant to assess postoperative RTS, timing of return, frequency and type of pre- and postoperative activities, and satisfaction (scored 1-10). Descriptive statistical analyses were performed, and regression models were developed to examine the influence of age and sex, as well as surgical site, on RTS. Results: A total of 53 patients (mean ± SD age, 73.8 ± 5.2 years; 24 women) were included, and 23 (43.4%) returned to sports at a median 6 months (interquartile range, IQR, 2-6 months). The RTS rate by surgical site was 17 of 34 (50%) for the lumbar spine and 6 of 17 (35.3%) for the cervical spine. There were no statistically significant differences in RTS rate by surgical site, age, or sex. Overall, 6 of 17 patients returned to golf, 4 of 6 to dance, 2 of 5 to swimming, and 1 of 5 to tennis. Of patients who returned, 34.8% participated in sports 5 times per week and 26.1% participated 3 times per week. The median satisfaction score after RTS was 8 (IQR, 6-9). Conclusion: RTS after spinal surgery was achieved in 43% patients at 1-year minimum follow-up, with high satisfaction scores. More than half of the returning patients participated in sports activities ≥3 times per week.

Arthroscopic treatment for Morel-Lavallée lesion of the thigh: A case report and literature review.

INTRODUCTION: Morel-Lavallée lesion (MLL) is a posttraumatic closed degloving soft tissue injury, in which the subcutaneous tissues are separated from the underlying fascia. Surgical treatment is recommended if conservative management fails. The conventional surgical treatment for the lesion is surgical drainage and debridement. PRESENTATION OF CASE: A 51-year-old male patient presented with swelling of the right thigh incurred during a traffic accident. The lesion was diagnosed with MLL. The MLL was successfully treated with a minimally invasive arthroscopic treatment after failure of conservative treatment. The arthroscopic treatment was chosen because of the patient's comorbidity that posed a risk of surgical wound complications. In addition, negative pressure wound therapy (NPWT) was performed postoperatively to ensure healing and to prevent recurrence of the lesion. The patient was successfully treated and the healing of the lesion was also confirmed with MRI. DISCUSSION: In a patient with a risk of wound complications due to a comorbidity, this minimally invasive arthroscopic treatment is useful. In addition, NPWT was used to ensure healing and to prevent recurrence. Although the use of NPWT combined with endoscopic treatment has not been reported, additional NPWT reported in this case may be helpful to ensure healing. CONCLUSION: In case of MLL with a risk of surgical complications, the arthroscopic treatment is a reasonable method and achieves the goal of an open surgical debridement without increased morbidity.

Dynamic Changes of Cauda Equina Motion Before and After Decompressive Laminectomy for Lumbar Spinal Stenosis With Redundant Nerve Roots: Cauda Equina Activation Sign.

STUDY DESIGN: Cross-sectional observational study (consecutive case series). OBJECTIVES: The aim of this study was to define a criterion for achieving successful decompression of lumbar spinal stenosis (LSS) using intraoperative ultrasonography (IOUS) and to investigate the pathogenesis of redundant nerve roots (RNRs) based on the ultrasonographic findings. METHODS: A total of 100 LSS patients (71 males, 29 females, mean age, 71 ± 8 years) with RNRs were enrolled as subjects in this study. IOUS was performed to evaluate pulsatile motion of the cauda equina (PMCE) just before and after decompressive laminectomy. To determine the decompression status of the cauda equina, the ultrasonographic findings were classified into 3 types on the basis of the presence or absence of PMCE: type 1, predecompression PMCE (-) to postdecompression PMCE (+); type 2, pre- and postdecompression PMCE (+); and type 3, pre- and postdecompression PMCE (-). The pathogenesis of RNRs was also investigated based on the ultrasonographic findings. RESULTS: Around the stenosis, PMCE was almost always absent before decompression and appeared after decompression (type 1 in 94 patients, type 2 in 6, type 3 in 0). IOUS showed that, before decompression, the cauda equina was held at the stenosis and could not pulsate beyond the stenotic site, and after decompression, PMCE recovered in the craniocaudal direction, leading to the resolution of RNRs. CONCLUSIONS: The emergence of PMCE can be a sign of successful decompression for LSS. Ultrasonographic findings support the notion that disturbance of PMCE around the stenosis is a basic component of the pathogenesis of RNRs.

The 25-question Geriatric Locomotive Function Scale predicts the risk of recurrent falls in postoperative patients with cervical myelopathy.

BACKGROUND: Fall-induced injuries represent a major public health concern for older individuals. The relationship between risk of falling and the severity of locomotive syndrome (LS) remains largely unknown. METHODS: We conducted a retrospective analysis of patients who had undergone surgery from January 2012 to December 2013 and completed at least 1 year of follow-up at 12 participating institutes. Patients completed a questionnaire survey regarding their fall experience during a routine postoperative follow-up. Questionnaire items included the number of falls during the prior postoperative year and the 25-question Geriatric Locomotive Function Scale (GLFS-25). The severity of cervical myelopathy was assessed using the Japanese Orthopaedic Association (JOA) score. We analyzed the association between the incidence of falling and the severity of LS measured by the GLFS-25. RESULTS: Of 360 patients, 61 (16.9%) experienced 1 fall; 31 (8.6%), 2-3 falls; 4 (1.1%), 4-5 falls; and 6 (1.7%), ≥6 falls during the first postoperative year. Thus, 102 (28%) patients experienced at least 1 fall, and 41 (11%) experienced recurrent falls (2 or more falls) during the time period. The mean GLFS-25 score was 30.2 ± 22.7, and 242 (62%) patients had GLFS-25 scores of 16 or higher, which fulfilled the diagnostic criteria for LS. When subjects were categorized into recurrent fallers and non-recurrent fallers, recurrent fallers had a significantly higher GLFS-25 score and a significantly lower extremity motor function score of the JOA score than non-recurrent fallers. The GLFS-25 and lower extremity motor function score of the JOA score yielded the areas under the receiver operating characteristic curves of 0.674 and 0.607, respectively, to differentiate recurrent fallers from non-recurrent fallers. CONCLUSION: Postoperative patients with cervical myelopathy had a 62% prevalence of LS. The GLFS-25 may be useful to predict the risk of recurrent falls in patients with cervical myelopathy.

Fall-related Deterioration of Subjective Symptoms in Patients with Cervical Myelopathy.

STUDY DESIGN: Retrospective multi-center study. OBJECTIVE: This study was conducted to clarify the incidence and neurological outcomes of fall-related deterioration of subjective symptoms in patients undergoing surgical treatment. SUMMARY OF BACKGROUND DATA: The evidence that minor trauma, including falls, increases the risk of worsening cervical myelopathy is insufficient. METHODS: A retrospective analysis of patients who had undergone surgery for cervical myelopathy at 12 participating institutes was conducted. Patients who had undergone surgery for symptomatic cervical myelopathy from January 2012 to December 2013 and completed at least 1-year follow-up were included in this study. Data were collected by chart review and a questionnaire that included numbers of recalled falls during the last preoperative year and first postoperative year, circumstances of falls, and whether the patient had experienced fall-related deterioration of subjective symptoms. RESULTS: A total of 360 eligible patients were recruited into the study. Of these, 177 (49%) reported at least one fall during the last preoperative year, and 105 (29%) experienced fall-related deterioration of subjective symptoms. Forty (11%) reported deterioration of numbness in the arms or legs, and 65 (18%) reported deterioration of motor deficits. Incidences of falls and fall-related deterioration of symptoms decreased significantly after surgery. Patients who experienced fall-related deterioration of motor deficits showed significantly worse surgical outcomes as assessed by Japanese Orthopaedic Association (JOA) score compared with those who did not experience deterioration. The optimal cut-off for preoperative JOA score in predicting an increased risk of fall-related deterioration in motor deficits was 8. CONCLUSION: Patients with cervical myelopathy commonly experienced preoperative fall-related deterioration of subjective symptoms, associated with significantly worse neurological outcomes. Surgical treatment significantly reduced the incidence of both falls and fall-related deterioration of subjective symptoms. LEVEL OF EVIDENCE: 4.

Klf1, a C2H2 zinc finger-transcription factor, is required for cell wall maintenance during long-term quiescence in differentiated G0 phase.

Fission yeast, Schizoaccharomyces pombe, is a model for studying cellular quiescence. Shifting to a medium that lacks a nitrogen-source induces proliferative cells to enter long-term G0 quiescence. Klf1 is a Krüppel-like transcription factor with a 7-amino acid Cys2His2-type zinc finger motif. The deletion mutant, ∆klf1, normally divides in vegetative medium, but proliferation is not restored after long-term G0 quiescence. Cell biologic, transcriptomic, and metabolomic analyses revealed a unique phenotype of the ∆klf1 mutant in quiescence. Mutant cells had diminished transcripts related to signaling molecules for switching to differentiation; however, proliferative metabolites for cell-wall assembly and antioxidants had significantly increased. Further, the size of ∆klf1 cells increased markedly during quiescence due to the aberrant accumulation of Calcofluor-positive, chitin-like materials beneath the cell wall. After 4 weeks of quiescence, reversible proliferation ability was lost, but metabolism was maintained. Klf1 thus plays a role in G0 phase longevity by enhancing the differentiation signal and suppressing metabolism for growth. If Klf1 is lost, S. pombe fails to maintain a constant cell size and normal cell morphology during quiescence.

Schizosaccharomyces pombe cell division cycle under limited glucose requires Ssp1 kinase, the putative CaMKK, and Sds23, a PP2A-related phosphatase inhibitor.

Calcium/calmodulin-dependent protein kinase (CaMK) is required for diverse cellular functions, and similar kinases exist in fungi. Although mammalian CaMK kinase (CaMKK) activates CaMK and also evolutionarily-conserved AMP-activated protein kinase (AMPK), CaMKK is yet to be established in yeast. We here report that the fission yeast Schizosaccharomyces pombe Ssp1 kinase, which controls G2/M transition and response to stress, is the putative CaMKK. Ssp1 has a CaM binding domain (CBD) and associates with 14-3-3 proteins as mammalian CaMKK does. Temperature-sensitive ssp1 mutants isolated are defective in the tolerance to limited glucose, and this tolerance requires the conserved stretch present between the kinase domain and CBD. Sds23, multi-copy suppressor for mutants defective in type 1 phosphatase and APC/cyclosome, also suppresses the ssp1 phenotype, and is required for the tolerance to limited glucose. We demonstrate that Sds23 binds to type 2A protein phosphatases (PP2A) and PP2A-related phosphatase Ppe1, and that Sds23 inhibits Ppe1 phosphatase activity. Ssp1 and Ppe1 thus seem to antagonize in utilizing limited glucose. We also show that Ppk9 and Ssp2 are the catalytic subunits of AMPK and AMPK-related kinases, respectively, which bind to common beta-(Amk2) and gamma-(Cbs2) subunits.

C/EBPbeta Promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57.

BACKGROUND: Although transition from proliferation to hypertrophic differentiation of chondrocytes is a crucial step for endochondral ossification in physiological skeletal growth and pathological disorders like osteoarthritis, the underlying mechanism remains an enigma. This study investigated the role of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) in chondrocytes during endochondral ossification. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryos with homozygous deficiency in C/EBPbeta (C/EBPbeta-/-) exhibited dwarfism with elongated proliferative zone and delayed chondrocyte hypertrophy in the growth plate cartilage. In the cultures of primary C/EBPbeta-/- chondrocytes, cell proliferation was enhanced while hypertrophic differentiation was suppressed. Contrarily, retroviral overexpression of C/EBPbeta in chondrocytes suppressed the proliferation and enhanced the hypertrophy, suggesting the cell cycle arrest by C/EBPbeta. In fact, a DNA cell cycle histogram revealed that the C/EBPbeta overexpression caused accumulation of cells in the G0/G1 fraction. Among cell cycle factors, microarray and real-time RT-PCR analyses have identified the cyclin-dependent kinase inhibitor p57(Kip2) as the transcriptional target of C/EBPbeta. p57(Kip2) was co-localized with C/EBPbeta in late proliferative and pre-hypertrophic chondrocytes of the mouse growth plate, which was decreased by the C/EBPbeta deficiency. Luciferase-reporter and electrophoretic mobility shift assays identified the core responsive element of C/EBPbeta in the p57(Kip2) promoter between -150 and -130 bp region containing a putative C/EBP motif. The knockdown of p57(Kip2) by the siRNA inhibited the C/EBPbeta-induced chondrocyte hypertrophy. Finally, when we created the experimental osteoarthritis model by inducing instability in the knee joints of adult mice of wild-type and C/EBPbeta+/- littermates, the C/EBPbeta insufficiency caused resistance to joint cartilage destruction. CONCLUSIONS/SIGNIFICANCE: C/EBPbeta transactivates p57(Kip2) to promote transition from proliferation to hypertrophic differentiation of chondrocytes during endochondral ossification, suggesting that the C/EBPbeta-p57(Kip2) signal would be a therapeutic target of skeletal disorders like growth retardation and osteoarthritis.

A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia.

The effectiveness and safety of yokukansan (TJ-54), a traditional Japanese medicine (kampo) for the treatment of the behavioural and psychological symptoms of dementia (BPSD), were evaluated in 106 patients diagnosed as having Alzheimer's disease (AD) (including mixed-type dementia) or dementia with Lewy bodies. Patients were randomly assigned to group A (TJ-54 treatment in period I and no treatment in period II; each period lasting 4 wk) or group B (no treatment in period I and TJ-54 treatment in period II). BPSD and cognitive functions were evaluated using the Neuropsychiatric Inventory (NPI) and the Mini-Mental State Examination (MMSE), respectively. Activities of daily living (ADL) were evaluated using Instrumental Activities of Daily Living (IADL) in outpatients and the Barthel Index in in-patients. For the safety evaluation, adverse events were investigated. Significant improvements in mean total NPI score associated with TJ-54 treatment were observed in both periods (Wilcoxon test, p=0.040 in period I and p=0.048 in period II). The mean NPI scores significantly improved during TJ-54 treatment in groups A and B (p=0.002 and p=0.007, respectively) but not during periods of no treatment. Among the NPI subscales, significant improvements were observed in delusions, hallucinations, agitation/aggression, depression, anxiety, and irritability/lability. The effects of TJ-54 persisted for 1 month without any psychological withdrawal symptoms in group A. TJ-54 did not show any effect on either cognitive function or ADL. No serious adverse reactions were observed. The present study suggests that TJ-54 is an effective and well-tolerated treatment for patients with BPSD.

Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9.

Although degradation of cartilage matrix has been suggested to be a rate-limiting step for endochondral ossification during skeletal development, little is known about the transcriptional regulation. This study investigated the involvement of KLF5 (Krüppel-like factor 5), an Sp/KLF family member, in the skeletal development. KLF5 was expressed in chondrocytes and osteoblasts but not in osteoclasts. The heterozygous deficient (KLF5+/-) mice exhibited skeletal growth retardation in the perinatal period. Although chondrocyte proliferation and differentiation were normal, cartilage matrix degradation was impaired in KLF5+/- mice, causing delay in replacement of cartilage with bone at the primary ossification center in the embryonic limbs and elongation of hypertrophic chondrocyte layer in the neonatal growth plates. Microarray analyses identified MMP9 (matrix metalloproteinase 9) as a transcriptional target, since it was strongly up-regulated by adenoviral transfection of KLF5 in chondrogenic cell line OUMS27. The KLF5 overexpression caused gelatin degradation by stimulating promoter activity of MMP9 without affecting chondrocyte differentiation or vascular endothelial growth factor expression in the culture of chondrogenic cells; however, in osteoclast precursors, it affected neither MMP9 expression nor osteoclastic differentiation. KLF5 dysfunction by genetic heterodeficiency or RNA interference was confirmed to cause reduction of MMP9 expression in cultured chondrogenic cells. MMP9 expression was decreased in the limbs of KLF5+/- embryos, which was correlated with suppression of matrix degradation, calcification, and vascularization. We conclude that KLF5 causes cartilage matrix degradation through transcriptional induction of MMP9, providing the first evidence that transcriptional regulation of a proteinase contributes to endochondral ossification and skeletal development.

Phosphorylation of GSK-3beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes.

cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase-3beta (GSK-3beta; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3beta was associated with enhanced hypertrophic differentiation. Furthermore, cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3beta. Analyses of mice with compound deficiencies in both protein kinases (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. We found that beta-catenin levels decreased in Prkg2(-/-) mice, while overexpression of cGKII increased the accumulation and transactivation function of beta-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3beta. These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.

Akt1 in osteoblasts and osteoclasts controls bone remodeling.

Bone mass and turnover are maintained by the coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts, under regulation of many systemic and local factors. Phosphoinositide-dependent serine-threonine protein kinase Akt is one of the key players in the signaling of potent bone anabolic factors. This study initially showed that the disruption of Akt1, a major Akt in osteoblasts and osteoclasts, in mice led to low-turnover osteopenia through dysfunctions of both cells. Ex vivo cell culture analyses revealed that the osteoblast dysfunction was traced to the increased susceptibility to the mitochondria-dependent apoptosis and the decreased transcriptional activity of runt-related transcription factor 2 (Runx2), a master regulator of osteoblast differentiation. Notably, our findings revealed a novel role of Akt1/forkhead box class O (FoxO) 3a/Bim axis in the apoptosis of osteoblasts: Akt1 phosphorylates the transcription factor FoxO3a to prevent its nuclear localization, leading to impaired transactivation of its target gene Bim which was also shown to be a potent proapoptotic molecule in osteoblasts. The osteoclast dysfunction was attributed to the cell autonomous defects of differentiation and survival in osteoclasts and the decreased expression of receptor activator of nuclear factor-kappaB ligand (RANKL), a major determinant of osteoclastogenesis, in osteoblasts. Akt1 was established as a crucial regulator of osteoblasts and osteoclasts by promoting their differentiation and survival to maintain bone mass and turnover. The molecular network found in this study will provide a basis for rational therapeutic targets for bone disorders.

Two-step, extensive alterations in the transcriptome from G0 arrest to cell division in Schizosaccharomyces pombe.

Body cells in multicellular organisms are in the G0 state, in which cells are arrested and terminally differentiated. To understand how the G0 state is maintained, the genes that are specifically expressed or repressed in G0 must be identified, as they control G0. In the fission yeast Schizosaccharomyces pombe, haploid cells are completely arrested under nitrogen source starvation with high viability. We examined the global transcriptome of G0 cells and cells on the course to resume vegetative growth. Approximately 20% of the transcripts of approximately 5000 genes increased or decreased more than fourfold in the two-step transitions that occur prior to replication. Of the top 30 abundant transcripts in G0, 23 were replaced by ribosome- and translation-related transcripts in the dividing vegetative state. Eight identified clusters with distinct alteration patterns of approximately 2700 transcripts were annotated by Gene Ontology. Disruption of 53 genes indicated that nine of them were necessary to support the proper G0 state. These nine genes included two C2H2 zinc finger transcription factors, a cyclin-like protein implicated in phosphorylation of RNA polymerase II, two putative autophagy regulators, a G-protein activating factor, and two CBS domain proteins, possibly involved in AMP-activated kinase.

[Recent advances in cartilage metabolism research].

The past few years have seen an enormous increase in the knowledge of the signaling pathways and the transcription factors that control endochondral bone development. Recent studies of rare chondrodysplasias that exhibit disproportionate dwarfism due to the impairment of endochondral ossification have identified many responsible genes and have clarified pathogenic mechanisms of these diseases by using molecular genetics and biology. The details of human diseases related to collagen type II alpha1 (COL2A1), collagen type X alpha1 (COL10A1), parathyroid hormone (PTH) /parathyroid hormone-related protein (PTHrP) receptor, guanylate cyclase B (GC-B), sry-box 9 (SOX9), runt-related transcription factor 2 (RUNX2), which play important roles in the process of endochondral ossification, will be outlined.

Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability.

OBJECTIVE: By producing instability in mouse knee joints, we attempted to determine the involvement of runt-related transcription factor 2 (RUNX-2), which is required for chondrocyte hypertrophy, in the development of osteoarthritis (OA). METHODS: An experimental mouse OA model was created by surgical transection of the medial collateral ligament and resection of the medial meniscus of the knee joints of heterozygous RUNX-2-deficient (Runx2+/-) mice and wild-type littermates. Cartilage destruction and osteophyte formation in the medial tibial cartilage were compared by histologic and radiographic analyses. Localization of type X collagen and matrix metalloproteinase 13 (MMP-13) was examined by immunohistochemistry. Localization of RUNX-2 was determined by X-Gal staining in heterozygous RUNX-2-deficient mice with the lacZ gene insertion at the Runx2-deletion site (Runx2+/lacZ). Messenger RNA levels of type X collagen, MMP-13, and RUNX-2 were examined by real-time reverse transcriptase-polymerase chain reaction analysis. RESULTS: RUNX-2 was induced in the articular cartilage of wild-type mice at the early stage of OA, almost simultaneously with type X collagen but earlier than MMP-13. Runx2+/- and Runx2+/lacZ mice showed normal skeletal development and articular cartilage; however, after induction of knee joint instability, they exhibited decreased cartilage destruction and osteophyte formation, along with reduced type X collagen and MMP-13 expression, as compared with wild-type mice. CONCLUSION: RUNX-2 contributes to the pathogenesis of OA through chondrocyte hypertrophy and matrix breakdown after the induction of joint instability.

Fission yeast MAP kinase is required for the increased securin-separase interaction that rescues separase mutants under stresses.

Sister chromatid separation requires two steps of proteolysis. Securin, the chaperon and inhibitor of separase, is destructed in anaphase after polyubiquitination, and resulting activated separase cleaves the cohesin subunit Scc1/Rad21. Fission yeast securin/Cut2 and separase/Cut1 that form the complex are essential for viability and a number of temperature-sensitive (ts) mutants have been isolated. We here report that the stresses such as 1.2 M sorbitol, 0.6 M KCl and 0.1 M CaCl(2) in the medium suppress the ts phenotypes of all the cut1 mutants and two of the three cut2 mutants examined. This unexpected finding led us to study how the ts phenotypes of cut1 and cut2 mutants were rescued by the increased stresses. The stresses caused a temporal arrest in the cell number increase, and this arrest was dependent on Spc1/Sty1 but not Rad3 and Mad2. During the 2-3 hr arrested period that occurred prior to the restart of division cycle, the level of securin dramatically increased, apparently accompanying the increased complex formation with mutant separase protein. Securin bound to separase was hyperphosphorylated. The stresses could not rescue the indestructible Cut2 and Rad21 mutants. We postulate that the stresses produce the hyperchaperonic form of Cut2 that can rescue separase mutations.

Carminerin contributes to chondrocyte calcification during endochondral ossification.

Endochondral ossification is an essential process not only for physiological skeletal development and growth, but also for pathological disorders. We recently identified a novel cartilage-specific molecule, carminerin (also known as cystatin 10 and encoded by Cst10), which is upregulated in synchrony with cartilage maturation and stimulates the later differentiation of cultured chondrocytes. Although carminerin-deficient (Cst10-/-) mice developed and grew normally, they had a microscopic decrease in the calcification of hypertrophic chondrocytes at the growth plate. When we created experimental models of pathological endochondral ossification, we observed suppression of chondrocyte calcification during formation of osteoarthritic osteophytes, age-related ectopic ossification and healing of bone fractures in Cst10-/- mice. Cultured Cst10-/- chondrocytes showed a reduction in calcification with activation of an SRY site in the promoter of the gene encoding nucleotide pyrophosphatase phosphodiesterase 1 (NPP1, encoded by Enpp1). Functional NPP1 is required for carminerin deficiency to suppress the pathological endochondral ossifications listed above. Carminerin is the first cartilage-specific protein that contributes to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.