M-CSF Priming of Osteoclast Precursors Can Cause Osteoclastogenesis-Insensitivity, Which Can be Prevented and Overcome on Bone

Osteoclasts and macrophages share progenitors that must receive decisive lineage signals driving them into their respective differentiation routes. Macrophage colony stimulation factor M-CSF is a common factor; bone is likely the stimulus for osteoclast differentiation. To elucidate the effect of both, shared mouse bone marrow precursor myeloid blast was pre-cultured with M-CSF on plastic and on bone. M-CSF priming prior to stimulation with M-CSF and osteoclast differentiation factor RANKL resulted in a complete loss of osteoclastogenic potential without bone. Such M-CSF primed cells expressed the receptor RANK, but lacked the crucial osteoclastogenic transcription factor NFATc1. This coincided with a steeply decreased expression of osteoclast genes TRACP and DC-STAMP, but an increased expression of the macrophage markers F4/80 and CD11b. Compellingly, M-CSF priming on bone accelerated the osteoclastogenic potential: M-CSF primed cells that had received only one day M-CSF and RANKL and were grown on bone already expressed an array of genes that are associated with osteoclast differentiation and these cells differentiated into osteoclasts within 2 days. Osteoclastogenesis-insensitive precursors grown in the absence of bone regained their osteoclastogenic potential when transferred to bone. This implies that adhesion to bone dictates the fate of osteoclast precursors. Common macrophage-osteoclast precursors may become insensitive to differentiate into osteoclasts and regain osteoclastogenesis when bound to bone or when in the vicinity of bone. J. Cell. Physiol. 229: 210-225, 2014. (c) 2014 Wiley Periodicals, Inc.

Exercise tolerance can be enhanced through a change in work rate within the severe intensity domain: work above critical power is not constant

The characterization of the hyperbolic power-time (P-tlim) relationship using a two-parameter model implies that exercise tolerance above the asymptote (Critical Power; CP), i.e. within the severe intensity domain, is determined by the curvature (W') of the relationship. The purposes of this study were (1) to test whether the amount of work above CP (W>CP) remains constant for varied work rate experiments of high volatility change and (2) to ascertain whether W' determines exercise tolerance within the severe intensity domain. Following estimation of CP (208 ± 19 W) and W' (21.4 ± 4.2 kJ), 14 male participants (age: 26 ± 3; peak [Formula: see text]: 3708 ± 389 ml.min-1) performed two experimental trials where the work rate was initially set to exhaust 70% of W' in 3 ('THREE') or 10 minutes ('TEN') before being subsequently dropped to CP plus 10 W. W>CP for TEN (104 ± 22% W') and W' were not significantly different (P>0.05) but lower than W>CP for THREE (119 ± 17% W', P<0.05). For both THREE (r = 0.71, P<0.01) and TEN (r = 0.64, P<0.01), a significant bivariate correlation was found between W' and tlim. W>CP and tlim can be greater than predicted by the P-tlim relationship when a decrement in the work rate of high-volatility is applied. Exercise tolerance can be enhanced through a change in work rate within the severe intensity domain. W>CP is not constant.