Functional Adaptation to Loading of a Single Bone Is Neuronally Regulated and Involves Multiple Bones

A brisk kick to the shin is a painful reminder that bone is rich in nerve endings, an attribute first described by the French anatomist, M Gros, in 1846. Half a century later, in 1892, the German anatomist, Julius Wolff, revealed the skeleton’s capacity to adapt to loading challenges, with bone added and/or removed to best accommodate changes in functional demands. Whereas the skeleton’s adaptive attributes have become integral to any strategy to retain bone quantity and quality in the face of aging and hormonal changes, this “form follows function” paradigm has challenged musculoskeletal biologists and bioengineers with identifying the cell population(s) and molecular mechanism(s) responsible for perceiving and responding to these mechanical stimuli. Not surprisingly, being that it was bone that was loaded and bone that was adapting, such studies have focused primarily on the resident bone cell population—osteoblasts, bone-lining cells, and osteocytes— as the obvious candidates responsible for assessing and regulating the tissue’s response to new mechanical demands. In work published in this issue of JBMR, Sample et al. provide provocative new evidence that the innervation of bone, described so well by Gros, may be a critical mediator of Wolff’s skeletal adaptation to mechanical signals. Through a carefully designed series of experiments, the authors first showed that an intense mechanical challenge can translate to a remote anabolic response as far away as the contralateral control limb. The authors then showed that active innervation is critical to the transformation of local loading into an adaptive event, local or remote, because a local anesthetic administered before the mechanical stimulation abrogates the bone modeling response. Like a kick in the shin, this paper reminds us that ensuring the adaptive capacity of the bone may not be the responsibility of bone cells alone, and instead may rely on input and/or control from other cell populations contributing to the musculoskeletal “system.” The experiment designed by the laboratory from the University of Wisconsin subjects the right ulna of anesthetized rats to a single bout of 1500 cycles of a load sufficient to cause either 760, 1500, or 3750 microstrain, reflecting low, medium, and very high levels of functionally induced strain, respectively. Ten days after load, examination of the ulna showed a pronounced increase in bone formation at specific sites around the periosteum, with the greater the strain challenge, the greater the response. In a surprising result, particularly evident in those animals subject to the supraphysiologic strain regimen, bone formation increased on the periosteal surface of the ipsilateral humerus, and as well, the authors found a significant modeling response in the contralateral ulna and humerus. This result directly contrasts with the generally held notion of a “local challenge, focal response” paradigm. Just as surprisingly, blockade of neuronal signaling between the loaded limb and the spinal cord by bupivacaine injection of the brachial plexus not only mitigated the periosteal response in the remote bones but in the directly loaded ulna. This work indicates that signals other than direct matrix strain are required for the modeling response and that cells beyond “simply” bone cells are involved in orchestrating bone adaptation. These provocative results invite reconsideration of some of our dearly held dogmas regarding mechanical adaptation of bone. Sample’s evidence of “remote” adaptation is in direct contrast to previously published, and well accepted, “unilateral” loading protocols and suggests that even if the physically challenged bone cells can perceive and respond to a load, that some x-factor is released to signal a remote, if not systemic response. Perhaps our failure to recognize a remote response in previous reports is as much because the measured responses were greater because of a more efficacious load regimen or the simple reason that a small response was simply not expected and thus inadvertently ignored. That said, investigators have looked specifically at the possibility of remote adaptive responses to local mechanical challenges and have concluded that, if the stimulus is local, the response is local. Certainly, it is possible that distant bones were inadvertently loaded in the current report or that the higher loads that were sufficiently “stimulatory” surpassed a threshold for “adaptation” and reached a level of “repair,” resulting in the release of inflammatory cytokines to cause a remote response. Assuredly, if Harold Frost was still with us, he would interpret the supraphysiologic strain regimen’s unique ability to stimulate “other than local” responses as evidence of a Dr Clinton Rubin is a founder of Juvent Medical. Dr Janet Rubin states that she has no conflicts of interest.