Anti-siglec-15 antibody prevents the marked bone loss after acute spinal cord injury-induced immobilization in rats

Authors: PENG, YUANZHEN - James J Peters Vamc; LANGERMANN, SOLOMON - Nextcure, Inc; KOTHARI, PRIYANKA - Nextcure, Inc; LIU, LINDA - Nextcure, Inc; ZHAO, WEI - James J Peters Vamc; HU, YIZHONG - Columbia University; CHEN, ZIHAO - Brown University; LI, JILIANG - Purdue University; Cao, Jay; GUO, X. EDWARD - Columbia University; CHEN, LIEPING - Yale School Of Medicine; BAUMAN, WILLIAM - James J Peters Vamc; QIN, WEIPING - James J Peters Vamc

Submitted to: Journal of Bone and Mineral Research Plus
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/13/2023
Publication Date: 9/27/2023
Citation: Peng, Y., Langermann, S., Kothari, P., Liu, L., Zhao, W., Hu, Y., Chen, Z., Li, J., Cao, J.J., Guo, X., Chen, L., Bauman, W.A., Qin, W. 2023. Anti-siglec-15 antibody prevents the marked bone loss after acute spinal cord injury-induced immobilization in rats. Journal of Bone and Mineral Research Plus. 7(12). Article e10825.

Interpretive Summary: There are approximately 288,000 people with spinal cord injury in the United States and spinal cord injury induces significant bone loss at approximately 1% per week at certain skeletal regions during the initial months. Antibody against Sialic acid-binding immunoglobulin-like lectin (Siglec)-15, a protein expressed on the mature osteoclast surface, can be useful in preventing acute spinal cord injury-induced bone loss. In this study, we demonstrated that Siglec-15 antibody reduced osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, prevented loss of bone mineral density and preserved bone strength in a rat model of acute spinal cord injury.

Technical Abstract: The rapid and extensive sublesional bone loss after spinal cord injury (SCI) is a difficult medical problem that has been refractory to available interventions except the potent anti-resorptive agent, denosumab. Sialic acid-binding immunoglobulin-like lectin (Siglec)-15 is expressed on the cell surface of mature osteoclasts. Anti-Siglec-15 antibody (Ab) has been shown to inhibit osteoclast maturation and bone resorption while maintaining osteoblast activity, which is distinct from current anti-resorptive agents that inhibit the activity of both osteoclasts and osteoblasts. The goal of the present study is to test Siglec-15 Ab (NP159) as a new treatment option to prevent bone loss in an acute SCI model. To this end, 4-month-old male Wistar rats underwent complete spinal cord transection. Immediately after SCI, rats were treated with either vehicle or NP159 at 20 mg/kg once every 2 weeks for 8 weeks. SCI resulted in significant decreases in bone mineral density (-18.7%), trabecular bone volume (-43.1%), trabecular connectivity (-59.7%), and bone stiffness (-76.3%) at the distal femur. Treatment with NP159 almost completely prevented the aforementioned deterioration of bone after SCI. Blood and histomorphometric analyses revealed that Siglec-15 Ab was able to greatly inhibit bone resorption while maintaining bone formation after acute SCI. In ex vivo cultures of bone marrow cells, NP159 reduced osteoclastogenesis while increasing osteoblastogenesis, thereby reversing the observed adverse cellular activity after SCI. In summary, treatment with NP159 fully prevents sublesional loss of BMD and metaphysis trabecular bone volume and preserves bone strength in a rat model of acute SCI. Because of its unique ability to reduce osteoclastogenesis and bone resorption while promoting osteoblastogenesis to maintain bone formation, Siglec-15 Ab may have greater potential as a therapeutic agent than those currently used exclusively anti-resorptive or anabolic agents to mitigate the striking bone loss associated with SCI or other conditions associated with severe immobilization.