STAT3 Hyperactivation Due to SOCS3 Deletion in Murine Osteocytes Accentuates Responses to Exercise- and Load-Induced Bone Formation

Abstract

Cortical bone develops and changes in response to mechanical load, which is sensed by bone-embedded osteocytes. The bone formation response to load depends on STAT3 intracellular signals, which are upregulated after loading and are subject to negative feedback from Suppressor of Cytokine Signaling 3 (Socs3). Mice with Dmp1Cre-targeted knockout of Socs3 have elevated STAT3 signaling in osteocytes and display delayed cortical bone maturation characterized by impaired accrual of high-density lamellar bone. This study aimed to determine whether these mice exhibit an altered response to mechanical load. The approach used was to test both treadmill running and tibial compression in female Dmp1Cre.Socs3 f/f mice. Treadmill running for 5 days per week from 6 to 11 weeks of age did not change cortical bone mass in control mice, but further delayed cortical bone maturation in Dmp1Cre. Socs3 f/f mice; accrual of high-density bone was suppressed, and cortical thickness was less than in genetically-matched sedentary controls. When strain-matched anabolic tibial loading was tested, both control and Dmp1Cre.Socs3 f/f mice exhibited a significantly greater cortical thickness and periosteal perimeter in loaded tibia compared with the contralateral non-loaded bone. At the site of greatest compressive strain, the loaded Dmp1Cre.Socs3 f/f tibias showed a significantly greater response than controls, indicated by a greater increase in cortical thickness. This was due to a greater bone formation response on both periosteal and endocortical surfaces, including formation of abundant woven bone on the periosteum. This suggests a greater sensitivity to mechanical load in Dmp1Cre.Socs3 f/f bone. In summary, mice with targeted SOCS3 deletion and immature cortical bone have an exaggerated response to both physiological and experimental mechanical loads. We conclude that there is an optimal level of osteocytic response to mechanical load required for cortical bone maturation and that load-induced bone formation may be increased by augmenting STAT3 signaling within osteocytes.

Suppressing STAT3 activation impairs bone formation during maxillary expansion and relapse

“… 23 STAT3 hyperactivation accentuates bone formation on the periosteal surface in response to mechanical stimuli. 24 During both the expansion and relapse periods of our study, STAT3 inactivation reduced migration of periosteal cells to the MPS and suppressed suture widening. Thus, the close relationship between STAT3 and periosteal cells may also impact bone formation in the MPS.…”

Exercise maintains bone homeostasis by promoting osteogenesis through STAT3

“…Recent studies showed that STAT3 was phosphorylated in response to mechanical loading in periodontal ligament cells and osteocytes and so on [26][27][28][29][30], and Stat3 in osteocytes was indicated to mediate osteogenic response to loading [29]. Others also demonstrated that load-induced bone formation may be increased by augmenting STAT3 signaling within osteocytes [31]. The osteoblastic STAT3 in BMSCs under mechanical force remains unclear.…”

Calcitriol-Dependent and -Independent Regulation of Intestinal Calcium Absorption, Osteoblast Function, and Skeletal Mineralization during Lactation and Recovery in Mice

“…Such overproduction of osteoid is also observed histologically in VDR null mice bred on a normocalcemic diet ( 7,25,30 ) and in the context of human vitamin D–dependent rickets type 2. ( 38‐40 ) The use of multiple thresholds, including a specific threshold for low‐density bone, was essential for rapidly identifying this phenotype by MCT. This highlights another useful application of this new method previously applied to understand changes in cortical bone development ( 36,37 ) and the response of young bone to treadmill running activity.…”