Osteocyte-Derived CaMKK2 Regulates Osteoclasts and Bone Mass in a Sex-Dependent Manner through Secreted Calpastatin.

Calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) regulates bone remodeling through its effects on osteoblasts and osteoclasts. However, its role in osteocytes, the most abundant bone cell type and the master regulator of bone remodeling, remains unknown. Here we report that the conditional deletion of CaMKK2 from osteocytes using Dentine matrix protein 1 (Dmp1)-8kb-Cre mice led to enhanced bone mass only in female mice owing to a suppression of osteoclasts. Conditioned media isolated from female CaMKK2-deficient osteocytes inhibited osteoclast formation and function in in vitro assays, indicating a role for osteocyte-secreted factors. Proteomics analysis revealed significantly higher levels of extracellular calpastatin, a specific inhibitor of calcium-dependent cysteine proteases calpains, in female CaMKK2 null osteocyte conditioned media, compared to media from female control osteocytes. Further, exogenously added non-cell permeable recombinant calpastatin domain I elicited a marked, dose-dependent inhibition of female wild-type osteoclasts and depletion of calpastatin from female CaMKK2-deficient osteocyte conditioned media reversed the inhibition of matrix resorption by osteoclasts. Our findings reveal a novel role for extracellular calpastatin in regulating female osteoclast function and unravel a novel CaMKK2-mediated paracrine mechanism of osteoclast regulation by female osteocytes.

The Effectiveness of Mindfulness- and Acceptance-Based Interventions for Informal Caregivers of People With Dementia: A Meta-Analysis.

BACKGROUND AND OBJECTIVES: The application of mindfulness- and acceptance-based interventions (MABIs) for informal caregivers of people with dementia (PwD) is relatively novel, and the current state of the evidence base is unclear. This meta-analysis examined the effectiveness of MABIs on reducing symptoms of depression and burden in informal caregivers of PwD. The quality of included studies was evaluated and moderator variables explored. RESEARCH DESIGN AND METHODS: A literature search of six electronic databases (PsycARTICLES, PsycINFO, MEDLINE Complete, SCOPUS, Web of Science, and ProQuest) was conducted from the first available date to 20 December 2016. Inclusion criteria involved studies that quantitatively investigated the impact of MABIs on depression and/or burden in informal caregivers of PwD. RESULTS: Twelve studies, providing data on 321 caregivers, were included. Most used mindfulness-based stress reduction and were conducted in the United States. The average attrition among participants was 15.83%. The pre-post effect of MABIs was large for depression and moderate for burden. These effects were largely maintained at follow-up. Significant heterogeneity of effect sizes was observed, with no significant moderators identified. Study quality varied from very poor to moderately good. DISCUSSION AND IMPLICATIONS: The low attrition and moderate to large effects suggest that MABIs are acceptable and beneficial for informal caregivers of PwD. The lack of significant moderators could advocate services using more cost-effective forms of MABIs. Further higher-quality research is needed to improve the robustness of the evidence base and enable a meta-analysis to thoroughly examine and quantify moderator variables.

The Evaluation of a Compassion-Focused Therapy Group for Couples Experiencing a Dementia Diagnosis.

OBJECTIVES: This study evaluated the effectiveness of a Compassion-Focused Therapy (CFT) group on reducing anxiety, depression, and respiratory rate (RR) in people with dementia (PwD) and their spouses, and improving quality of life (QoL) of PwD. METHOD: Sixty-four participants completed six weekly CFT sessions. Baseline and post-intervention assessments were analyzed using t-tests and Reliability Change Index. RESULTS: Mean baseline and post-assessment anxiety and depression scores fell in the 'normal range'; although a significant reduction in depression with moderate effect was observed for PwD. Fifty-seven percent of PwD with borderline to abnormal baseline scores showed clinically significant improvement in anxiety and depression. For spouses, 80% showed clinically significant improvement in depression and 50% in anxiety. RR reduced for PwD and spouses with large and medium effects respectively. QoL of PwD improved with a large effect. CONCLUSIONS: CFT appears effective in improving QoL and depression in PwD and reducing RR in PwD and spouses. CFT reduces anxiety and depression in most PwD and spouses with borderline to abnormal symptoms. CLINICAL IMPLICATIONS: This study indicates benefits of a group-CFT intervention delivered to people with a range of dementia diagnosis and their spouses. The service should investigate whether individuals in greater distress are not accessing the group and improve engagement.