Theoretical Schemas to Guide Back Pain Consortium (BACPAC) Chronic Low Back Pain Clinical Research.

BACKGROUND: Chronic low back pain (cLBP) is a complex with a heterogenous clinical presentation. A better understanding of the factors that contribute to cLBP is needed for accurate diagnosis, optimal treatment, and identification of mechanistic targets for new therapies. The Back Pain Consortium (BACPAC) Research Program provides a unique opportunity in this regard, as it will generate large clinical datasets, including a diverse set of harmonized measurements. The Theoretical Model Working Group was established to guide BACPAC research and to organize new knowledge within a mechanistic framework. This article summarizes the initial work of the Theoretical Model Working Group. It includes a three-stage integration of expert opinion and an umbrella literature review of factors that affect cLBP severity and chronicity. METHODS: During Stage 1, experts from across BACPAC established a taxonomy for risk and prognostic factors (RPFs) and preliminary graphical depictions. During Stage 2, a separate team conducted a literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to establish working definitions, associated data elements, and overall strength of evidence for identified RPFs. These were subsequently integrated with expert opinion during Stage 3. RESULTS: The majority (∼80%) of RPFs had little strength-of-evidence confidence, whereas seven factors had substantial confidence for either a positive association with cLBP (pain-related anxiety, serum C-reactive protein, diabetes, and anticipatory/compensatory postural adjustments) or no association with cLBP (serum interleukin 1-beta / interleukin 6, transversus muscle morphology/activity, and quantitative sensory testing). CONCLUSION: This theoretical perspective will evolve over time as BACPAC investigators link empirical results to theory, challenge current ideas of the biopsychosocial model, and use a systems approach to develop tools and algorithms that disentangle the dynamic interactions among cLBP factors.

Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice.

The osteocyte network is crucial for the response of bone to mechanical force. Within this network, connexin43 (Cx43) is thought to mediate the communication of osteocytes and osteoblasts among themselves and the exchange of small molecules with the extracellular milieu. Despite recent advances in understanding Cx43 role for the response of bone cells to mechanical stimulation, the contribution of Cx43 specifically in osteocytes to mechanotransduction in vivo is not well-known. We examined the anabolic response to ulnar axial loading of mice lacking Cx43 in osteocytes (Cx43(ΔOt)). Loading induced a greater increase in periosteal bone formation rate in Cx43(ΔOt) mice compared to control littermates, resulting from higher mineralizing surface and enhanced mineral apposition rate. Expression of ß-catenin protein, a molecule implicated in mechanotransduction, was higher in bones from Cx43(ΔOt) mice, compared to littermate controls. In addition, MLO-Y4 osteocytic cells knocked-down for Cx43 exhibited higher ß-catenin protein expression and enhanced response to mechanical stimulation. These findings suggest that osteocytes lacking Cx43 are "primed" to respond to mechanical stimulation and that absence of Cx43 in osteocytes unleashes bone formation, by a mechanism that might involve accumulation of ß-catenin.

Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation.

Connexin 43 (Cx43) mediates osteocyte communication with other cells and with the extracellular milieu and regulates osteoblastic cell signaling and gene expression. We now report that mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes (Cx43(ΔOt) mice) exhibit increased osteocyte apoptosis, endocortical resorption, and periosteal bone formation, resulting in higher marrow cavity and total tissue areas measured at the femoral mid-diaphysis. Blockade of resorption reversed the increased marrow cavity but not total tissue area, demonstrating that endocortical resorption and periosteal apposition are independently regulated. Anatomical mapping of apoptotic osteocytes, osteocytic protein expression, and resorption and formation suggests that Cx43 controls osteoclast and osteoblast activity by regulating osteoprotegerin and sclerostin levels, respectively, in osteocytes located in specific areas of the cortex. Whereas empty lacunae and living osteocytes lacking osteoprotegerin were distributed throughout cortical bone in Cx43(ΔOt) mice, apoptotic osteocytes were preferentially located in areas containing osteoclasts, suggesting that osteoclast recruitment requires active signaling from dying osteocytes. Furthermore, Cx43 deletion in cultured osteocytic cells resulted in increased apoptosis and decreased osteoprotegerin expression. Thus, Cx43 is essential in a cell-autonomous fashion in vivo and in vitro for osteocyte survival and for controlling the expression of osteocytic genes that affect osteoclast and osteoblast function.