Linda and Mitch Hart Center for Regenerative and Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA.
Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
Int J Mol Sci. 2023 Jan 25;24(3):2396. doi: 10.3390/ijms24032396.
Osteoporosis and age-related bone loss increase bone fracture risk and impair bone healing. The need for identifying new factors to prevent or treat bone loss is critical. Previously, we reported that young MRL/MpJ mice have superior bone microarchitecture and biomechanical properties as compared to wild-type (WT) mice. In this study, MRL/MpJ mice were tested for resistance to age-related and long-term ovariectomy-induced bone loss to uncover potential beneficial factors for bone regeneration and repair. Bone tissues collected from 14-month-old MRL/MpJ and C57BL/6J (WT) mice were analyzed using micro-CT, histology, and immunohistochemistry, and serum protein markers were characterized using ELISAs or multiplex assays. Furthermore, 4-month-old MRL/MpJ and WT mice were subjected to ovariectomy (OV) or sham surgery and bone loss was monitored continuously using micro-CT at 1, 2, 4, and 6 months (M) after surgery with histology and immunohistochemistry performed at 6 M post-surgery. Sera were collected for biomarker detection using ELISA and multiplex assays at 6 M after surgery. Our results indicated that MRL/MpJ mice maintained better bone microarchitecture and higher bone mass than WT mice during aging and long-term ovariectomy. This resistance of bone loss observed in MRL/MpJ mice correlated with the maintenance of higher OSX osteoprogenitor cell pools, higher activation of the pSMAD5 signaling pathway, more PCNA cells, and a lower number of osteoclasts. Systemically, lower serum RANKL and DKK1 with higher serum IGF1 and OPG in MRL/MpJ mice relative to WT mice may also contribute to the maintenance of higher bone microarchitecture during aging and less severe bone loss after long-term ovariectomy. These findings may be used to develop therapeutic approaches to maintain bone mass and improve bone regeneration and repair due to injury, disease, and aging.
骨质疏松症和与年龄相关的骨质流失增加了骨折风险，并损害了骨骼愈合。因此，确定预防或治疗骨质流失的新因素至关重要。此前，我们曾报道过，与野生型（WT）小鼠相比，年轻的 MRL/MpJ 小鼠具有更优越的骨微观结构和生物力学特性。在这项研究中，我们对 MRL/MpJ 小鼠进行了测试，以研究其对与年龄相关的和长期卵巢切除引起的骨质流失的抗性，以揭示潜在的有益于骨骼再生和修复的因素。使用微 CT、组织学和免疫组织化学分析来自 14 月龄的 MRL/MpJ 和 C57BL/6J（WT）小鼠的骨组织，并使用 ELISA 或多重分析测定血清蛋白标志物。此外，对 4 月龄的 MRL/MpJ 和 WT 小鼠进行卵巢切除术（OV）或假手术，并在手术后 1、2、4 和 6 个月（M）使用微 CT 连续监测骨丢失，在手术后 6 M 进行组织学和免疫组织化学检查。在手术后 6 M 时，使用 ELISA 和多重分析测定血清生物标志物。我们的结果表明，在衰老和长期卵巢切除期间，MRL/MpJ 小鼠保持了比 WT 小鼠更好的骨微观结构和更高的骨量。在 MRL/MpJ 小鼠中观察到的这种抗骨丢失现象与维持更高的 OSX 成骨前体细胞池、更高的 pSMAD5 信号通路活性、更多的 PCNA 细胞和更少的破骨细胞相关。在系统水平上，与 WT 小鼠相比，MRL/MpJ 小鼠的血清 RANKL 和 DKK1 较低，血清 IGF1 和 OPG 较高，这也可能有助于在衰老期间维持更高的骨微观结构和在长期卵巢切除后减轻更严重的骨质流失。这些发现可用于开发治疗方法，以维持骨量并改善因受伤、疾病和衰老而导致的骨再生和修复。
