The pericellular matrix (PCM), a thin “coating” surrounding nearly all mammalian cells, plays a critical role in many cell-surface phenomena. In osteocytes, the PCM is believed to control both “outside-in” (mechanosensing) and “inside-out” (signaling molecule transport) processes. However, the osteocytic PCM is challenging to study in situ because it is thin (~100nm) and enclosed in mineralized matrix. To this end, we recently developed a novel tracer velocimetry approach that combined fluorescence recovery after photobleaching (FRAP) imaging with hydrodynamic modeling to quantify the osteocytic PCM in young murine bone (Wang et al., J Bone Miner Res. 2013; 28:1075–86). In this study, we applied the technique to older mice expressing or deficient for perlecan/HSPG2, a large heparan-sulfate proteoglycan normally secreted in osteocytic PCM. The objectives were to i) characterize transport within an altered PCM; ii) to test the sensitivity of our approach in detecting the PCM alterations; and iii) to dissect the roles of the PCM in osteocyte mechanosensing. We found that i) solute transport increases in the perlecan-deficient (hypomorphic: Hypo) mice compared with control mice; ii) PCM fiber density decreases with aging and perlecan deficiency; iii) the osteocytes in the Hypo bones are predicted to experience higher shear stress (+34%), but decreased fluid drag force (−35%) under 3N peak tibial loading, and iv) when subjected to tibial loading in a preliminary in vivo experiment, the Hypo mice did not respond to the anabolic stimuli as CTL mice. These findings support the hypothesis that the PCM fibers act as osteocyte’s sensing antennae, regulating load-induced cellular stimulations and thus bone’s sensitivity and in vivo bone adaptation. If this hypothesis is further confirmed, osteocytic PCM could be new targets to develop osteoporosis treatments by modulating bone’s intrinsic sensitivity to mechanical loading and be used to design patient-specific exercise regimens to promote bone formation.

Each year, 33% of US citizens suffer from a musculoskeletal condition that requires medical intervention, with direct medical costs approaching $1 trillion USD per year. Despite the ubiquity of skeletal dysfunction, there are currently limited safe and efficacious bone growth factors in clinical use. Notch is a cell–cell communication pathway that regulates self-renewal and differentiation within the mesenchymal/osteoblast lineage. The principal Notch ligand in bone, Jagged-1, is a potent osteoinductive protein that positively regulates post-traumatic bone healing in animals. This report describes the temporal regulation of Notch during intramembranous bone formation using marrow ablation as a model system and demonstrates decreased bone formation following disruption of Jagged-1 in mesenchymal progenitor cells. Notch gain-of-function using recombinant Jagged-1 protein on collagen scaffolds promotes healing of craniofacial (calvarial) and appendicular (femoral) surgical defects in both mice and rats. Localized delivery of Jagged-1 promotes bone apposition and defect healing, while avoiding the diffuse bone hypertrophy characteristic of the clinically problematic bone morphogenetic proteins. It is concluded that Jagged-1 is a bone-anabolic agent with therapeutic potential for regenerating traumatic or congenital bone defects.

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PGC-1 (peroxisome-proliferator-activated receptor-γ coactivator-1) alpha is a potent transcriptional coactivator that coordinates the activation of numerous metabolic processes. Exercise strongly induces PGC-1alpha expression in muscle, and overexpression of PGC-1alpha in skeletal muscle activates mitochondrial oxidative metabolism and neovascularization, leading to markedly increased endurance. In light of these findings, PGC-1alpha has been proposed to protect from age-associated sarcopenia, bone loss, and whole-body metabolic dysfunction, although these findings have been controversial. We therefore comprehensively evaluated muscle and whole-body function and metabolism in 24-month-old transgenic mice that over-express PGC-1alpha in skeletal muscle. We find that the powerful effects of PGC-1alpha on promoting muscle oxidative capacity and protection from muscle fatigability persist in aged animals, although at the expense of muscle strength. However, skeletal muscle PGC-1alpha does not prevent bone loss and in fact accentuates it, nor does it have long-term benefit on whole-body metabolic composition or insulin sensitivity. Protection from sarcopenia is seen in male animals with overexpression of PGC-1alpha in skeletal muscle but not in female animals. In summary, muscle-specific expression of PGC-1alpha into old age has beneficial effects on muscle fatigability and may protect from sarcopenia in males, but does not improve whole-body metabolism and appears to worsen age-related trabecular bone loss.

We thank Loucks and colleagues for their commentary on our recent review summarizing the methods that are currently available to evaluate bone strength and fracture risk in the clinical setting. In addition to the techniques discussed in our review [1], the mechanical response tissue analysis (MRTA) method described by Loucks et al. shows great promise in providing a non-invasive, in vivo evaluation of bone stiffness. MRTA assesses tibial/ulnar bending stiffness through analysis of the bone's frequency response to vibrational loading [2], which has been shown to be highly predictive of the whole-bone stiffness measured through three-point bending [3]. In addition, in vivo studies have indicated that MRTA is able to detect a reduced ulnar stiffness in aged and osteoporotic subjects [4, 5], indicating its relevance to the clinical setting. We anticipate the application of the further enhanced Cortical Bone Mechanics Technology (CBMT) described by Arnold et al. [6] to a clinical model in the near future. References 1. de Bakker CM, Tseng WJ, Li Y, Zhao H, Liu XS. Clinical evaluation of bone strength and fracture risk. Curr Osteoporos Rep. 2017;15(1): 32-42. 2. Miller LE, Ramp WK, Steele CR, Nickols-Richardson SM, Herbert WG. Rationale, design and clinical performance of the mechanical response tissue analyser: a non-invasive technology for measurement of long bone bending stiffness. J Med Eng Technol. 2013;37(2):144-9. 3. Roberts SG, Hutchinson TM, Arnaud SB, et al. Noninvasive determination of bone mechanical properties using vibration response: a refined model and validation in vivo. J Biomech. 1996;29(1):91-8. 4. Kiebzak GM, Box JH, Box P. Decreased ulnar bending stiffness in osteoporotic Caucasian women. J Clin Densitom. 1999;2(2):143-52. 5. McCabe F, Zhou LJ, Steele CR, Marcus R. Noninvasive assessment of ulnar bending stiffness in women. J Bone Miner Res. 1991;6(1): 53-9. 6. Arnold PA, Ellerbrock ER, Bowman L, Loucks AB. Accuracy and reproducibility of bending stiffness measurements by mechanical response tissue analysis in artificial human ulnas. J Biomech. 2014;47(14):3580-3. This reply refers to the comment available at