Previous studies have shown that transforming growth factor β (TGF-β) promotes receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclastogenesis. However, the underlying molecular mechanisms have not been elucidated. When TGF-β signals were blocked either by a specific inhibitor of TGF-β type 1 receptor kinase activity, SB431542, or by introducing a dominant-negative mutant of TGF-β type 2 receptor, RANKL-induced osteoclastogenesis was almost completely suppressed. Blockade of Smad signaling by overexpression of Smad7 or c-Ski markedly suppressed RANKL-induced osteoclastogenesis, and retroviral induction of an activated mutant of Smad2 or Smad3 reversed the inhibitory effect of SB431542. Immunoprecipitation analysis revealed that Smad2/3 directly associates with the TRAF6-TAB1-TAK1 molecular complex, which is generated in response to RANKL stimulation and plays an essential role in osteoclast differentiation. TRAF6-TAB1-TAK1 complex formation was not observed when TGF-β signaling was blocked. Analysis using deletion mutants revealed that the MH2 domain of Smad3 is necessary for TRAF6-TAB1-TAK1 complex formation, downstream signal transduction, and osteoclast formation. In addition, gene silencing of Smad3 in osteoclast precursors markedly suppressed RANKL-induced osteoclast differentiation. In summary, TGF-β is indispensable in RANKL-induced osteoclastogenesis, and the binding of Smad3 to the TRAF6-TAB1-TAK1 complex is crucial for RANKL-induced osteoclastogenic signaling. © 2011 American Society for Bone and Mineral Research.

A retrospective comparative study. To investigate natural course and prognostic factors in patients with mild forms of cervical spondylotic myelopathy (CSM), focusing on intramedullary increased signal intensity (ISI) on T2-weighted magnetic resonance imaging. Long-term natural course of mild forms of CSM, especially with ISI on magnetic resonance imaging, remains uncertain. Patients with CSM who visited our institution between 1992 and 2004 and did not undergo surgery at first visit were retrospectively reviewed. The inclusion criteria were as follows: (1) motor function Japanese Orthopedic Association scores of 3 or more in both upper and lower extremities and (2) cervical spinal cord compression with ISI on T2-weighted magnetic resonance imaging. There were 45 patients, with a mean follow-up period of 78 months (range, 24-208). We investigated long-term natural history by setting the timing of conversion to surgery due to neurological deterioration as an end point. We further compared prognostic parameters between patients who converted to surgery and those who continued to be followed up nonsurgically. Sixteen patients gradually deteriorated and underwent decompression surgery, whereas 27 patients did not. Apart from these, 2 patients with acute spinal cord injury after minor trauma underwent surgery. Kaplan-Meier survival analysis revealed that 82% or 56% of patients did not require surgery 5 or 10 years after the initial treatment, respectively. As for prognostic factors, Cox proportional hazard analysis revealed that total cervical range of motion (hazard ratio: 3.25), segmental kyphosis in the maximum compression segment (hazard ratio: 4.51), and local slip (hazard ratio: 4.67) were statistically significant. Fifty-six percent of patients with clinically mild CSM with ISI had not deteriorated or undergone surgery at 10 years. Large range of motion, segmental kyphosis, and instability at the narrowest canal were considered to be adverse prognostic factors.

Ectopic endochondral ossification in the tendon/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive ( ⁺ ) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct Prg4 ⁺ TSPC cluster. The Rspo2 ⁺ cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression. RSPO2 expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor κB. Rspo2 ⁺ cells may contribute to tendon/ligament homeostasis under pathogenic conditions.

Although the efficiency of conservative management for lumbar spinal stenosis (LSS) has been examined, different conservative management approaches have not been compared. We have performed the first comparative trial of three types of conservative management (medication with acetaminophen, exercise, and acupuncture) in Japanese patients with LSS. Patients with L5 root radiculopathy associated with LSS who visited our hospital for surgical treatment were enrolled between December 2011 and January 2014. In this open-label study, patients were assigned to three treatment groups (medication, exercise, acupuncture) according to the visit time. The primary outcomes were Zurich claudication questionnaire (ZCQ) scores before and after 4 weeks of treatment. Least square mean analysis was used to assess the following dependent variables in the treatment groups: changes in symptom severity and physical function scores of the ZCQ and the ZCQ score of patient’s satisfaction after treatment. Thirty-eight, 40, and 41 patients were allocated to the medication, exercise, and acupuncture groups, respectively. No patient underwent surgical treatment during the study period. The symptom severity scores of the ZCQ improved significantly after treatment in the medication (p = 0.048), exercise (p = 0.003), and acupuncture (p = 0.04) groups. The physical function score improved significantly in the acupuncture group (p = 0.045) but not in the medication (p = 0.20) and exercise (p = 0.29) groups. The mean reduction in the ZCQ score for physical function was significantly greater for acupuncture than for exercise. The mean ZCQ score for treatment satisfaction was significantly greater for acupuncture than for medication. Acupuncture was significantly more effective than physical exercise according to the physical function score of the ZCQ and than medication according to the satisfaction score. The present study provides new important information that will aid decision making in LSS treatment. This study was registered with the UMIN Clinical Trials Registry ( UMIN000006957 ).

Study Design: A retrospective cohort study. Objective: To investigate whether the Japanese Orthopaedic Association (JOA) score can be used for patients with degenerative cervical myelopathy as a patient-reported outcome (PRO) through the JOA written questionnaire. Methods: A total of 75 patients who underwent posterior decompression surgery for degenerative cervical myelopathy were reviewed. Patients responded to questionnaires including PRO-JOA, EuroQOL-5D, Neck Disability Index, and Short Form-12 preoperatively and at >12 months postoperatively. Spearman’s rho and Bland-Altman analyses were used to investigate the correlations. Results: Preoperative JOA and PRO-JOA scores were 10.8 and 10.6, respectively, with Spearman’s rho of 0.74. Similarly, postoperative JOA and PRO-JOA scores were 13.3 and 12.9, respectively, with Spearman’s rho of 0.68. However, the recovery rates for JOA and PRO-JOA scores were 42% and 27%, respectively, with Spearman’s rho of 0.45. Compared with other PROs, JOA and PRO-JOA scores were moderately correlated. The minimum clinically important difference was 2.5 for JOA score, 3.0 for PRO-JOA score, 42% for JOA recovery rate, and 33% for PRO-JOA recovery rate. Bland-Altman analyses revealed that limits of agreement were −4.3 to 4.7, −3.4 to 4.3, and −75% to 106% for the preoperative score, postoperative score, and recovery rate, respectively. Conclusion: PRO-JOA score can also be used as a disease-specific scoring measure instead of JOA score. However, although both measures demonstrate a similar trend as a group analysis, PRO-JOA and JOA scores should be regarded as different outcomes.