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靶向外侧下丘脑 MCH 神经内分泌回路以预防骨骼衰老。

Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence.

机构信息

Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.

Department of Orthopedic Trauma, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China.

出版信息

Adv Sci (Weinh). 2024 Nov;11(43):e2309951. doi: 10.1002/advs.202309951. Epub 2024 Sep 25.

DOI:10.1002/advs.202309951
PMID:39320347
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11578307/
Abstract

Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain-bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.

摘要

神经内分泌调节对于维持代谢稳态至关重要。然而，神经内分泌途径是否影响骨代谢和骨骼衰老尚不清楚。本研究鉴定出一个中枢神经内分泌回路，该回路可直接控制成骨作用。通过病毒示踪，本研究发现位于下丘脑外侧（LH）的黑色素浓缩激素（MCH）表达神经元与骨骼相连。LH 中 MCH 神经元的化学遗传激活诱导成骨作用，而抑制这些神经元则减少成骨作用。同时，这些神经元的化学遗传激活会导致 MCH 释放到循环中。单细胞测序揭示，LH 中 MCH 神经元的阻断会抑制骨髓基质细胞（BMSC）的成骨分化，并诱导衰老。在机制上，MCH 通过 PKA 信号激活 MCHR1 促进 BMSC 分化，而 MCH 激动剂激活 MCHR1 则可以减轻小鼠的骨骼衰老。通过阐明自主增强成骨作用的脑-骨连接，这些发现揭示了调节骨量的神经内分泌机制，并可预防骨骼衰老。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/88f3199e63d5/ADVS-11-2309951-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/186424490f5c/ADVS-11-2309951-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/a96e3d4d0f29/ADVS-11-2309951-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/b1362048d5b3/ADVS-11-2309951-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/15c725132684/ADVS-11-2309951-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/2ffe7fa5e54a/ADVS-11-2309951-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/34df265c5c90/ADVS-11-2309951-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/b8a25e221925/ADVS-11-2309951-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/88f3199e63d5/ADVS-11-2309951-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/186424490f5c/ADVS-11-2309951-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/a96e3d4d0f29/ADVS-11-2309951-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/b1362048d5b3/ADVS-11-2309951-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/15c725132684/ADVS-11-2309951-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/2ffe7fa5e54a/ADVS-11-2309951-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/34df265c5c90/ADVS-11-2309951-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/b8a25e221925/ADVS-11-2309951-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80d3/11578307/88f3199e63d5/ADVS-11-2309951-g007.jpg

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