Metaphyseal and diaphyseal bone loss in the tibia following transient muscle paralysis are spatiotemporally distinct resorption events.
When the skeleton is catabolically challenged, there is great variability in the timing and extent of bone resorption observed at cancellous and cortical bone sites. It remains unclear whether this resorptive heterogeneity, which is often evident within a single bone, arises from increased permissiveness of specific sites to bone resorption or localized resorptive events of varied robustness. To explore this question, we used the mouse model of calf paralysis induced bone loss, which results in metaphyseal and diaphyseal bone resorption of different timing and magnitude. Given this phenotypic pattern of resorption, we hypothesized that bone loss in the proximal tibia metaphysis and diaphysis occurs through resorption events that are spatially and temporally distinct. To test this hypothesis, we undertook three complimentary in vivo/μCT imaging studies. Specifically, we defined spatiotemporal variations in endocortical bone resorption during the 3weeks following calf paralysis, applied a novel image registration approach to determine the location where bone resorption initiates within the proximal tibia metaphysis, and explored the role of varied basal osteoclast activity on the magnitude of bone loss initiation in the metaphysis using μCT based bone resorption parameters. A differential response of metaphyseal and diaphyseal bone resorption was observed throughout each study. Acute endocortical bone loss following muscle paralysis occurred almost exclusively within the metaphyseal compartment (96.5% of total endocortical bone loss within 6days). Using our trabecular image registration approach, we further resolved the initiation of metaphyseal bone loss to a focused region of significant basal osteoclast function (0.03mm(3)) adjacent to the growth plate. This correlative observation of paralysis induced bone loss mediated by basal growth plate cell dynamics was supported by the acute metaphyseal osteoclastic response of 5-week vs. 13-month-old mice. Specifically, μCT based bone resorption rates normalized to initial trabecular surface (BRRBS) were 3.7-fold greater in young vs. aged mice (2.27±0.27μm(3)/μm(2)/day vs. 0.60±0.44μm(3)/μm(2)/day). In contrast to the focused bone loss initiation in the metaphysis, diaphyseal bone loss initiated homogeneously throughout the long axis of the tibia predominantly in the second week following paralysis (81.3% of diaphyseal endocortical expansion between days 6 and 13). The timing and homogenous nature are consistent with de novo osteoclastogenesis mediating the diaphyseal resorption. Taken together, our data suggests that tibial metaphyseal and diaphyseal bone loss induced by transient calf paralysis are spatially and temporally discrete events. In a broader context, these findings are an essential first step toward clarifying the timing and origins of multiple resorptive events that would require targeting to fully inhibit bone loss following neuromuscular trauma.
Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA. Electronic address: bjausk@u.washington.edu.
Brandon J
BJ
Ausk
Philippe
P
Huber
Sundar
S
Srinivasan
Steven D
SD
Bain
Ronald Y
RY
Kwon
Erin A
EA
McNamara
Sandra L
SL
Poliachik
Christian L
CL
Sybrowsky
Ted S
TS
Gross
D000818:Animals; D001862:Bone Resorption / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology*; D018483:Diaphyses / Q000000981:diagnostic imaging / Q000503:physiopathology*; D051379:Mice; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000503:physiopathology*; D010243:Paralysis / Q000150:complications* / Q000000981:diagnostic imaging / Q000503:physiopathology*; D013977:Tibia / Q000000981:diagnostic imaging / Q000503:physiopathology*; D013997:Time Factors; D055114:X-Ray Microtomography
Bone; Bone resorption; Image registration; MicroCT; Muscle paralysis; Osteoclast